KR20240034160A - CD71 binding fibronectin type 3 domain - Google Patents

Abstract

The present disclosure relates to polypeptides, such as fibronectin type III (FN3) domain capable of binding CD71, conjugates thereof, isolated nucleotides encoding molecules, vectors, host-cells, as well as methods of making and using the same. will be.

Description

CD71 binding fibronectin type III domain

Related applications

This application claims priority to U.S. Provisional Patent Application No. 63/174,752, filed April 14, 2021, and U.S. Provisional Patent Application No. 63/324,431, filed March 28, 2022, which are incorporated in their entirety. is incorporated herein by reference.

sequence list

This application contains a sequence listing that has been filed electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy, created on May 17, 2022, is named 145965_002002_SL.txt and is 283,204 bytes in size.

technology field

This embodiment relates to a fibronectin type III domain (FN3) that specifically binds to cluster of differentiation 71 (CD71) and methods of making and using the molecule.

CD71, also known as transferrin receptor 1, is an essential transmembrane transport of iron into cells. It is highly expressed in many tumor types and the blood brain barrier, making it an important target for drug delivery. After binding to iron-containing transferrin, CD71 is rapidly endocytosed and efficiently recycled back to the cell surface. Studies on CD71 antibody drug conjugates suggest that targeting CD71 may improve the specificity and selectivity of drug delivery and broaden the therapeutic index. Additionally, studies using anti-CD71 monoclonal antibodies indicate that binding affinity may play an important role in enabling tissue-specific delivery, including smooth muscle or skeletal muscle delivery and transcytosis across the blood brain barrier. . Antibodies with high affinity for CD71 are rapidly internalized and alter normal receptor trafficking such that instead of recycling, the receptor is targeted to lysosomes for degradation. In contrast, antibodies with lower affinity for CD71 allow for receptor recycling and higher brain exposure.

While antibodies or antibody fragments are the most widely used class of therapeutic proteins when high affinity and specificity for target molecules are required, non-antibody proteins can also be engineered to bind such targets. These “alternative scaffold” proteins have advantages over traditional antibodies due to their small size, lack of disulfide bonds, high stability, ability to be expressed in prokaryotic hosts, easy purification, and they are easily conjugated to drugs/toxins and can be used in tissues. It penetrates efficiently and is easily formulated into a multispecific binder.

One of these alternative scaffolds is the immunoglobulin (Ig) fold. These folds are found not only in the variable regions of antibodies, but also in thousands of non-antibody proteins. One of these Ig proteins, the 10th fibronectin type III (FN3) repeat of human fibronectin, has been shown to be able to tolerate multiple mutations in surface-exposed loops while maintaining the overall Ig-folded structure. Therefore, what is needed is a FN3 domain capable of specifically binding to CD71 and a method of using these molecules for novel therapeutics that allows intracellular access through receptor-mediated internalization of CD71.

In some embodiments, an FN3 domain (e.g., polypeptide) that specifically binds to the CD71 protein is provided. In some embodiments, the FN3 domain is isolated. In some embodiments, the FN3 domain is recombinant. In some embodiments, the FN3 domain is non-naturally occurring.

In some embodiments, an FN3 domain comprising the amino acid sequence of SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306, 292 to 299, or 304 to 306 or 304 to 306. This is provided. In some embodiments, the FN3 domain binds CD71. In some embodiments, the FN3 domain binds human CD71 at a site on CD71 that does not compete with transferrin binding to CD71. In some embodiments, the FN3 domain specifically binds CD71. In some embodiments, polypeptides are provided comprising more than one FN3 domain linked by a linker, such as a flexible linker. In some embodiments, the polypeptide comprises two, three or four FN3 domains linked to each other by one or more linkers between the domains.

In some embodiments, an isolated polypeptide encoding a FN3 domain described herein is provided.

In some embodiments, vectors comprising polynucleotides described herein are provided.

In some embodiments, host cells comprising vectors described herein are provided.

In some embodiments, methods of producing an FN3 domain are provided. In some embodiments, the method includes culturing a host cell comprising a vector encoding or expressing an FN3 domain. In some embodiments, the method further includes purifying the FN3 domain. In some embodiments, the FN3 domain specifically binds CD71.

In some embodiments, pharmaceutical compositions are provided comprising an FN3 domain that binds CD71 and a pharmaceutically acceptable carrier.

In some embodiments, an anti-idiotypic antibody is provided that binds the FN3 domain that binds CD71.

In some embodiments, kits comprising one or more of the FN3 domains are provided.

In some embodiments, methods for detecting CD71-expressing cancer cells in tumor tissue are provided. In some embodiments, the method comprises obtaining a sample of tumor tissue from the subject, and the sample of tumor tissue having a sample of SEQ ID NO: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299 or 304 to 306 or 304 to 306. Detecting whether the CD71 protein is expressed in the tumor tissue by contacting the FN3 domain that binds to the CD71 protein comprising one of the amino acid sequences and detecting the binding between the CD71 protein and the FN3 domain.

In some embodiments, methods of isolating CD71 expressing cells are provided. In some embodiments, the method includes obtaining a sample from a subject; contacting the sample with an FN3 domain that binds to a CD71 protein comprising the amino acid sequence of one of SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299 or 304 to 306 or 304 to 306, and FN3 and isolating cells bound to the domain.

In some embodiments, methods for detecting CD71-expressing cancer cells in tumor tissue are provided. In some embodiments, the method comprises an FN3 domain that binds to a CD71 protein comprising the amino acid sequence of one of SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299 or 304 to 306 or 304 to 306. Forming a conjugate by conjugating it to a detectable label; administering the conjugate to the subject; and visualizing CD71-expressing cancer cells to which the zygote is bound.

In some embodiments, methods of treating cancer in a subject in need thereof are provided. In some embodiments, the method includes administering to the subject a polypeptide or pharmaceutical composition that binds CD71. In some embodiments, the polypeptide of interest is an FN3 domain that binds CD71. In some embodiments, the polypeptide is a sequence such as SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306, or a polypeptide as provided herein linked or conjugated to a therapeutic agent. Contains peptides.

In some embodiments, the polypeptide that binds CD71 is directed to the central nervous system. In some embodiments, methods of treating a neurological condition and/or brain tumor in a subject in need thereof are provided. In some embodiments, the method includes administering to the subject a polypeptide or pharmaceutical composition that binds CD71. In some embodiments, the polypeptide of interest is an FN3 domain that binds CD71. In some embodiments, the polypeptide is a sequence such as SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306, or a polypeptide as provided herein linked or conjugated to a therapeutic agent. Contains peptides. In some embodiments, the brain tumor is selected from the group consisting of non-malignant, benign, and malignant brain tumors. In some embodiments, the neurological condition is Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Lafora disease, Pompe disease, adult polyglucosanoma disease, stroke, spinal cord injury, ataxia, Bell's palsy, cerebral aneurysm, epilepsy, It is selected from the group consisting of seizures, Guillain-Barre syndrome, multiple sclerosis, muscular dystrophy, neurocutaneous syndrome, migraine, encephalitis, sepsis and myasthenia gravis.

In some embodiments, the polypeptide that binds CD71 is directed to muscle cells. In some embodiments, the method includes administering to the subject a polypeptide or pharmaceutical composition that binds CD71. In some embodiments, the polypeptide of interest is an FN3 domain that binds CD71. In some embodiments, the polypeptide is a sequence such as SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306, or a polypeptide as provided herein linked or conjugated to a therapeutic agent. Contains peptides.

In some embodiments, a method of treating Pompe disease (GSD2, acid alpha-glycosidase (GAA) deficiency) in a subject in need thereof is provided. In some embodiments, the method includes administering to the subject a polypeptide or pharmaceutical composition that binds CD71. In some embodiments, the polypeptide of interest is an FN3 domain that binds CD71. In some embodiments, the polypeptide is a sequence such as SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306, or a polypeptide as provided herein linked or conjugated to a therapeutic agent. Contains peptides.

In some embodiments, a method of treating a glycogen storage disease in a subject in need thereof is provided comprising administering a composition provided herein. In some embodiments, the glycogen storage disease is Cory's disease or Forbes' disease (GSD3, glycogen debranching enzyme (AGL) deficiency), McArdle disease (GSD5, muscle glycogen phosphorylase (PYGM) deficiency), type II diabetes/ Diabetic nephropathy, aldolase A deficiency GSD12, Lafora disease, hypoxia, Andersen's disease (GSD4, glycogen debranching enzyme (GBE1) deficiency), Tarui disease (GSD7, muscle phosphofructokinase (PFKM) deficiency) and adult poly. It is selected from the group consisting of gluconate body diseases. In some embodiments, the glycogen storage disease is glycogen synthase (GYS2) deficiency (GSD0), glucose-6-phosphatase (G6PC/SLC37A4) deficiency (GSD1, Von Gierke disease), Huss disease (GSD6, liver glycogen phosphorylation) Relays (PYGL) or muscle phosphoglycerate mutase (PGAM2) deficiency), phosphorylase kinase (PHKA2/PHKB/PHKG2/PHKA1) deficiency (GSD9), phosphoglycerate mutase (PGAM2) Deficiency (GSD10), muscle lactate dehydrogenase (LDHA) deficiency (GSD11), Fanconi-Bickel syndrome (GSD 11, glucose transporter (GLUT2) deficiency, aldolase A deficiency (GSD 12), β-enolase (ENO3) deficiency (GSD13) and glycogenin-1 (GYG1) deficiency (GSD15).

In some embodiments, the polypeptide that binds CD71 is directed against immune cells. In some embodiments, the polypeptide that binds CD71 is directed against dendritic cells, T-cells, NK cells, or B-cells. In some embodiments, methods of treating an autoimmune disease in a subject in need thereof are provided. In some embodiments, the method includes administering to the subject a polypeptide or pharmaceutical composition that binds CD71. In some embodiments, the polypeptide of interest is an FN3 domain that binds CD71. In some embodiments, the polypeptide is a sequence such as SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306, or a polypeptide as provided herein linked or conjugated to a therapeutic agent. Contains peptides. In some embodiments, the autoimmune disease is from the group consisting of rheumatoid arthritis, Hashimoto's autoimmune thyroiditis, celiac disease, type 1 diabetes, vitiligo, rheumatic fever, pernicious anemia/atrophic gastritis, alopecia areata, and immune thrombocytopenic purpura. is selected.

In some embodiments, methods of delivering an agent of interest to CD71 positive cells are provided. In some embodiments, the method comprises contacting the cell with an agent of interest coupled to the FN3 domain that binds CD71, such as a polypeptide as provided herein. In some embodiments, the agent of interest is a chemotherapeutic agent, drug, growth inhibitor, toxin, radioisotope, anti-tubulin agent, polynucleotide, siRNA molecule, antisense molecule, RNA molecule, DNA molecule, DNA minor groove binder, DNA replication agent. They are inhibitors, alkylating agents, antibiotics, antifolates, antimetabolites, chemotherapy sensitizers, topoisomerase inhibitors or vinca alkaloids.

In some embodiments, an FN3 domain provided herein is conjugated to a polynucleotide, siRNA molecule, antisense molecule, RNA molecule, or DNA molecule.

In some embodiments, the polypeptide is an FN3 protein that binds CD71 at a site that does not compete with or inhibit transferrin binding to CD71.

In some embodiments, methods are provided for identifying FN3 protein that binds CD71 at a site that does not compete with or inhibit transferrin binding to CD71.

Figure 1 illustrates quantification of AHA1 mRNA in various tissues of CD-1 mice following administration of FN3 polypeptide (ABX1007) or FN3 polypeptide-siRNA conjugate (ABX1005).
Figure 2 illustrates dose-dependent quantification of AHA1 mRNA in various tissues of C57BL6 mice following administration of FN3-siRNA conjugate (ABX1005).
Figure 3 provides the results of a target binding assay using over 6,000 receptors in the proteome array, with data showing that CD71 is the exclusive binding target of the FN3 domain.
Figure 4 provides data showing that CD71 centirin conjugate induces sustained gene knockdown compared to mAb conjugate at 2, 4, and 8 weeks post administration.
Figure 5 provides ELISA data showing that centirin and centirin conjugates actively bind to human and cynomolgus monkey CD71.
Figure 6 provides data showing the ability of the centirin-siRNA AHA1 conjugate to effectively knock down mRNA levels in vivo in cynomolgus monkey muscle and heart.

As used in this specification and the appended claims, “the singular form” includes plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a cell” includes a combination of two or more cells, etc.

“Fibronectin type III (FN3) domain” (FN3 domain) refers to a domain that frequently occurs in proteins including fibronectin, tenascin, intracellular cytoskeletal proteins, cytokine receptors, and prokaryotic enzymes (Bork and Doolittle, Proc Nat Acad Sci USA 89:8990-8994, 1992; Meinke et al ., J Bacteriol 175:1910-1918, 1993; Watanabe et al., J Biol Chem 265:15659-15665, 1990). Exemplary FN3 domains include the 15 different FN3 domains present in human tenascin C, the 15 different FN3 domains present in human fibronectin (FN), and as described, e.g., in U.S. Pat. No. 8,278,419. It is a non-natural synthetic FN3 domain. Individual FN3 domains are referred to by domain number and protein name, e.g., the 3rd FN3 domain of tenascin (TN3) or the 10th FN3 domain of fibronectin (FN10).

The term “capture agent” refers to a substance that binds to a specific type of cell and allows that cell to be isolated from other cells. Exemplary capture agents include magnetic beads, ferrofluids, encapsulation reagents, molecules that bind to specific cell types, etc.

“Sample” refers to a collection of body fluids, cells, or tissues present within a subject as well as similar body fluids, cells, or tissues isolated from the subject. Exemplary samples include tissue biopsies, fine needle aspirates, surgically excised tissue, organ cultures, cell cultures, and biological fluids such as blood, serum and serous fluids, plasma, lymph, urine, saliva, cystic fluid, tear drops, and stool. , sputum, mucous secretions from secretory tissues and organs, vaginal secretions, ascites fluid, pleural fluid, pericardium, peritoneum, abdomen and other body cavities, body fluids collected by bronchial lavage, joint sac fluid, objects or biological sources, e.g. It is a liquid solution in contact with cell and organ culture media, including cell or organ conditioned media and wash solutions.

“Substituting” or “substituted” or “mutating” or “mutated” refers to altering, deleting or inserting one or more amino acids or nucleotides in a polypeptide or polynucleotide sequence to create a variant of the sequence. do.

“Variant” refers to a polypeptide or polynucleotide that differs from a reference polypeptide or reference polynucleotide by one or more modifications, such as substitutions, insertions, or deletions.

“Specifically bind” or “specific binding” means less than or equal to about 1×10 ⁻⁶ M, for example, about 1×10 ⁻⁷ M Below, approximately 1×10 ^-8 M Below, approximately 1×10 ^-9 M Below, approximately 1×10 ^-10 M or below, approximately 1×10 ^-11 M Hereinafter, it refers to the ability of the FN3 domain to bind to a target such as CD71 with a dissociation constant (K _D ) of about 1×10 ^-12 M or less or about 1×10 ^-13 M or less. Alternatively, “specific binding” refers to the ability of the FN3 domain to bind a target (e.g., CD71) at least 5-fold higher than the negative control in a standard solution ELISA assay. Specific binding can also be demonstrated using proteomic arrays as described herein and shown in Figure 3. In some embodiments, the negative control is an FN3 domain that does not bind CD71. In some embodiments, the FN3 domain that specifically binds to CD71 may be linked to another related antigen, e.g., Macaca fascicularis (cynomolgus monkey, Cyno) or Panthroglodi. There may be cross-reactivity to the same predetermined antigen from another species (homolog), such as Pan troglodytes (chimpanzee).

“Library” refers to a collection of variants. Libraries may be comprised of polypeptide or polynucleotide variants.

“Stability” refers to the ability of a molecule to remain folded under physiological conditions so as to maintain at least one of its normal functional activities, e.g., binding to a predetermined antigen, such as CD71.

“CD71” refers to the human CD71 protein having the amino acid sequence of SEQ ID NO: 274 or 275. In some embodiments, SEQ ID NO:274 is a full-length human CD71 protein. In some embodiments, SEQ ID NO: 275 is the extracellular domain of human CD71.

SEQ ID NO: 274 = Human mature CD71

SEQ ID NO: 275 = Human mature CD71 extracellular domain

“tencon” refers to the synthetic fibronectin type III (FN3) domain having the sequence shown in SEQ ID NO: 276 and is described in US Publication No. 2010/0216708.

SEQ ID NO: 276 = Original Tencon Sequence

“Cancer cell” or “tumor cell” refers to a cancerous, precancerous or transformed cell in vivo, in vitro and in tissue culture that has spontaneous or induced phenotypic changes that do not necessarily involve uptake of new genetic material. do. Transformation can occur due to infection by a transgenic virus and integration of new genomic nucleic acids or uptake of exogenous nucleic acids, but it can also occur spontaneously or after exposure to carcinogens, resulting in mutations in endogenous genes. Transformation/cancer includes, for example, morphological changes in vitro, in vivo and ex vivo, immortalization of cells, abnormal growth control, lesion formation, proliferation, malignancy, tumor specific marker levels, invasiveness, nude mice. Examples include tumor growth or inhibition in a suitable animal host, such as (Freshney, Culture of Animal Cells: A Manual of Basic Technique (3rd ed. 1994)).

“Dendritic cells” refers to a type of antigen-presenting cell (APC) that forms an important role in the adaptive immune system. The main function of dendritic cells is to present antigens. Dendritic cells have the ability to induce primary immune responses from inactive or dormant naïve T lymphocytes.

“Immune cells” refers to cells of the immune system that are classified as lymphocytes (T-cells, B-cells, and NK cells), neutrophils, or monocytes/macrophages. These are all types of white blood cells.

“Vector” refers to a polynucleotide that can replicate within or move between biological systems. Vector polynucleotides typically contain elements such as origins of replication, polyadenylation signals, or selectable markers that function to facilitate replication or maintenance of such polynucleotides in biological systems. Examples of such biological systems may include reconstituted biological systems that utilize biological components capable of replicating cells, viruses, animals, plants, and vectors. The polynucleotide containing the vector may be a DNA or RNA molecule or a hybrid thereof.

“Expression vector” refers to a vector that can be utilized in a biological system or reconstituted biological system to direct the translation of a polypeptide encoded by a polynucleotide sequence present in the expression vector.

“Polynucleotide” refers to a synthetic molecule comprising a chain of nucleotides covalently linked by a sugar-phosphate backbone or other equivalent covalent chemistry. cDNA is a typical example of a polynucleotide.

“Polypeptide” or “protein” refers to a molecule containing at least two amino acid residues linked by peptide bonds to form a polypeptide. Small polypeptides consisting of less than about 50 amino acids may be referred to as “peptides.”

“Valence” refers to the presence of a specified number of binding sites specific for an antigen in a molecule. Likewise, the terms “monovalent,” “bivalent,” “tetravalent,” and “hexavalent” refer to the presence of 1, 2, 4, and 6 antigen-specific binding sites, respectively, in the molecule. .

“Subject” includes any human or non-human animal. “Non-human animals” includes all vertebrates, such as mammals, and non-mammals such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc. Except where noted, the terms “patient” or “subject” are used interchangeably.

“Isolated” refers to a molecule (e.g., a synthetic polynucleotide or polypeptide such as an FN3 domain) that has been substantially separated and/or purified from other components of the system in which the molecule is produced, such as a recombinant cell, as well as at least one purified or isolated It refers to a homogeneous population of proteins that have gone through several stages. An “isolated FN3 domain” is one that is substantially free of other cellular substances and/or chemicals and is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90 %, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% purity. .

Composition of the substance

In some embodiments, a protein comprising a polypeptide comprising the amino acid sequence of SEQ ID NOs: 1-7, 10, 12-219, 221-272, 292-299, or 304-306 is provided.

In some embodiments, the protein comprises a polypeptide comprising the amino acid sequence of SEQ ID NO:273. SEQ ID NO: 273 is a consensus sequence based on the sequences of SEQ ID NO: 288, SEQ ID NO: 289, SEQ ID NO: 290, and SEQ ID NO: 291.

The sequence of SEQ ID NO: 273 is:

Here, X ₈ , X ₉ , X ₁₇ and X ₁₈ are each independently any amino acid except methionine or proline, and

X ₁ is selected from D, F, Y or H,

X ₂ is selected from Y, G, A or V,

X ₃ is selected from I, T, L, A or H,

X ₄ is selected from S, Y or P,

X ₅ is selected from Y, G, Q or R,

X ₆ is selected from G or P,

X ₇ is selected from A, Y, P, D or S,

X ₁₀ is selected from W, N, S or E,

X ₁₁ is selected from L, Y or G,

X ₁₂ is is selected from D, Q, H or V,

X ₁₃ is selected from G or S,

X ₁₄ is selected from R, G, F, L or D,

X ₁₅ is selected from W, S, P or L, and

x ₁₆ silver Selected from T, V, M or S.

In some embodiments:

X ₁ is selected from D, F, Y or H,

X ₂ is selected from G, A or V,

X ₃ is selected from T, L, A or H,

X ₄ is selected from Y or P,

X ₅ is selected from G, Q or R,

X ₆ is selected from G or P,

X ₇ is selected from Y, P, D or S,

X ₁₀ is selected from W, N, S or E,

X ₁₁ is selected from L, Y or G,

X ₁₂ is selected from Q, H or V,

X ₁₃ is selected from G or S,

X ₁₄ is selected from G, F, L or D,

X ₁₅ is selected from S, P or L, and

x ₁₆ silver Selected from V, M or S.

_{In some embodiments ,} X ₅ , X ₆ , X ₇ , X ₁₀ , X ₁₁ , X ₁₂ , X ₁₃ , _{X 14 , In some embodiments ,} X ₅ , X ₆ , X ₇ , X ₁₀ , X ₁₁ , X ₁₂ , X ₁₃ , _{X 14 , In some embodiments ,} X ₅ , X ₆ , X ₇ , X ₁₀ , X ₁₁ , X ₁₂ , X ₁₃ , _{X 14 , In some embodiments ,} X ₅ , X ₆ , X ₇ , X ₁₀ , X ₁₁ , X ₁₂ , _{X 13} , X _{14 ,}

In some embodiments _{, X 8 ,} , tryptophan, tyrosine or valine. In some embodiments _{, X 8 ,} , not tryptophan, tyrosine or valine. In some embodiments, X ₈ , X ₉ , X ₁₇ and X ₁₈ are independently alanine. In some embodiments, X ₈ , X ₉ , X ₁₇ and X ₁₈ are independently arginine. In some embodiments, X ₈ , X ₉ , X ₁₇ and X ₁₈ are independently asparagine. In some embodiments, X ₈ , X ₉ , X ₁₇ and X ₁₈ are independently aspartic acid. In some embodiments, X ₈ , X ₉ , X ₁₇ and X ₁₈ are independently cysteine. In some embodiments, X ₈ , X ₉ , X ₁₇ and X ₁₈ are independently glutamine. In some embodiments, X ₈ , X ₉ , X ₁₇ and X ₁₈ are independently glutamic acids. In some embodiments, X ₈ , X ₉ , X ₁₇ and X ₁₈ are independently glycine. In some embodiments, X ₈ , X ₉ , X ₁₇ and X ₁₈ are independently histidine. In some embodiments, X ₈ , X ₉ , X ₁₇ and X ₁₈ are independently isoleucine. In some embodiments, X ₈ , X ₉ , X ₁₇ and X ₁₈ are independently leucine. In some embodiments, X ₈ , X ₉ , X ₁₇ and X ₁₈ are independently lysines. In some embodiments, X ₈ , X ₉ , X ₁₇ and X ₁₈ are independently phenylalanine. In some embodiments, X ₈ , X ₉ , X ₁₇ and X ₁₈ are independently serine. In some embodiments, X ₈ , X ₉ , X ₁₇ and X ₁₈ are independently threonines. In some embodiments, X ₈ , X ₉ , X ₁₇ and X ₁₈ are independently tryptophan. In some embodiments, X ₈ , X ₉ , X ₁₇ and X ₁₈ are independently tyrosines. In some embodiments, X ₈ , X ₉ , X ₁₇ and X ₁₈ are independently valine.

In some embodiments, _{the sequence} may be any other amino acid residue as set forth above _, except that the positions corresponding _to the positions _of It is presented as shown in the sequence of SEQ ID NO: 288, except that X ₉ is not T, X ₁₇ is not S, and X ₁₈ is not I.

In some embodiments, _{the sequence} may be any other amino acid residue as set forth above _, except that the positions corresponding _to the positions _of It is presented as shown in the sequence of SEQ ID NO: 289, except that X ₉ is not T, X ₁₇ is not S, and X ₁₈ is not I.

In some embodiments, _{the sequence} may be any other amino acid residue as set forth above _, except that the positions corresponding _to the positions _of It is presented as shown in the sequence of SEQ ID NO: 290 except that X ₉ is not T, X ₁₇ is not S, and X ₁₈ is not I.

In some _{embodiments , the sequence is} It is presented as shown in the sequence of SEQ ID NO: 291 except that X ₉ is not T, X ₁₇ is not S, and X ₁₈ is not I.

In some embodiments, the protein has at least 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90% , 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical amino acid sequences. In some embodiments, the protein is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical. In some embodiments, the protein is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO:273. In some embodiments, the protein is at least 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO:273. In some embodiments, the protein or polypeptide is at least 70%, 75%, 80%, 85%, or 90% identical to SEQ ID NO:273.

Percent identity can be determined using default parameters to align two sequences using BlastP, available through the NCBI website.

Polypeptides provided herein may be part of larger polypeptides and may be referred to as domains. Homology or identity between two domains of different polypeptides is based on similar domains as opposed to the entire polypeptide. For example, if the polypeptide comprises a polypeptide comprising an FN3 domain comprising SEQ ID NO: 1 and that domain is conjugated to an scFV antibody, then another protein having a domain similar to but not identical to SEQ ID NO: 1 would be an scFV Even if they do not share homology, they may be at least 90% identical. Accordingly, percent identity can be based on the domain or overall length of the polypeptide. Methods for determining percent identity are provided herein or are known to those skilled in the art.

In some embodiments, a fibronectin type III (FN3) domain is provided that binds or specifically binds human CD71 protein (SEQ ID NO: 274 or 275). As provided herein, the FN3 domain can bind CD71 protein. Additionally, although not explicitly stated, the domain may specifically bind to the CD71 protein. Thus, for example, an FN3 domain that binds to CD71 will also include a FN3 domain protein that specifically binds to CD71. These molecules can be used, for example, in therapeutic and diagnostic applications and imaging. In some embodiments, polynucleotides encoding the FN3 domains disclosed herein or complementary nucleic acids, vectors, host cells, and methods of making and using the same are provided.

In some embodiments, an isolated FN3 domain that binds or specifically binds CD71 is provided.

In some embodiments, the FN3 domain comprises two FN3 domains connected by a linker. The linker may be a flexible linker. The linker may be a short peptide sequence such as those described herein. For example, the linker may be a G/S linker, etc.

In some embodiments, the FN3 domain comprises two FN3 domains connected by a linker as provided herein. Exemplary linkers include (GS)2 (SEQ ID NO: 278), (GGGS)2 (SEQ ID NO: 279), (GGGGS)1-5 (SEQ ID NO: 280), (AP)1-20 (SEQ ID NO: 311); (AP)2 (SEQ ID NO: 281), (AP)5 (SEQ ID NO: 282), (AP) ₁₀ (SEQ ID NO: 283), (AP) ₂₀ (SEQ ID NO: 284), A(EAAAK) ₅ AAA (SEQ ID NO: 285) ) or (EAAAK) _1-5 (SEQ ID NO: 307). In some embodiments, the linker is EAAAKEAAAAKEAAAAKEAAAK (SEQ ID NO: 300); GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 301); APAPAPAPAP (SEQ ID NO: 302); or EAAAK (SEQ ID NO: 303) or its amino acid sequence.

In some embodiments, the polypeptide comprises the amino acid sequence of SEQ ID NO:292. In some embodiments, the polypeptide comprises the amino acid sequence of SEQ ID NO:293. In some embodiments, the polypeptide comprises the amino acid sequence of SEQ ID NO:294. In some embodiments, the polypeptide comprises the amino acid sequence of SEQ ID NO:295. In some embodiments, the polypeptide comprises the amino acid sequence of SEQ ID NO:296. In some embodiments, the polypeptide comprises the amino acid sequence of SEQ ID NO:297. In some embodiments, the polypeptide comprises the amino acid sequence of SEQ ID NO: 298. In some embodiments, the polypeptide comprises the amino acid sequence of SEQ ID NO:299.

In some embodiments, the FN3 domain is less than about 1×10 ⁻⁷ M, e.g., less than about 1×10 ⁻⁸ M, about 1, as determined by surface plasmon resonance or Kinexa methods as practiced by those skilled in the art. With ^a dissociation constant ^{( K D} ₎ of less ^than Can bind to CD71. The measured affinity of a particular FN3 domain-antigen interaction may vary when measured under various conditions (eg, osmolarity, pH). Accordingly, measurements of affinity and other antigen-binding parameters (e.g., K _D , K _on , K _off ) can be performed with standardized solutions of protein scaffold and antigen and with standardized buffers, such as those described herein. It comes true.

In some embodiments, the FN3 domain is capable of binding CD71 at least 5-fold greater than the signal obtained for a negative control in a standard solution ELISA assay.

In some embodiments, the FN3 domain that binds or specifically binds CD71 comprises an initiator methionine (Met) linked to the N-terminus of the molecule. In some embodiments, the FN3 domain that binds or specifically binds CD71 comprises a cysteine (Cys) linked to the C-terminus of the FN3 domain. Addition of N-terminal Met and/or C-terminal Cys can promote expression and/or conjugation of half-life extending molecules.

The FN3 domain may also include cysteine substitutions, such as those described in U.S. Pat. No. 10,196,446, which is incorporated herein by reference in its entirety. Briefly, in some embodiments, the polypeptides provided herein have sequences 6, 8, 10, 11, 14, and 15 of the FN3 domain based on SEQ ID NO: 6 or SEQ ID NO: 1 of U.S. Patent No. 10,196,446. , 16th, 20th, 30th, 34th, 38th, 40th, 41st, 45th, 47th, 48th, 53rd, 54th, 59th, 60th, 62nd, 64th, 70 It may contain at least one cysteine substitution at a position selected from the group consisting of residues 88, 89, 90, 91 and 93, and at an equivalent position in the related FN3 domain. In some embodiments, the substitution is at residue 6. In some embodiments, the substitution is at residue 8. In some embodiments, the substitution is at residue 10. In some embodiments, the substitution is at residue 11. In some embodiments, the substitution is at residue 14. In some embodiments, the substitution is at residue 15. In some embodiments, the substitution is at residue 16. In some embodiments, the substitution is at residue 20. In some embodiments, the substitution is at residue 30. In some embodiments, the substitution is at residue 34. In some embodiments, the substitution is at residue 38. In some embodiments, the substitution is at residue 40. In some embodiments, the substitution is at residue 41. In some embodiments, the substitution is at residue 45. In some embodiments, the substitution is at residue 47. In some embodiments, the substitution is at residue 48. In some embodiments, the substitution is at residue 53. In some embodiments, the substitution is at residue 54. In some embodiments, the substitution is at residue 59. In some embodiments, the substitution is at residue 60. In some embodiments, the substitution is at residue 62. In some embodiments, the substitution is at residue 64. In some embodiments, the substitution is at residue 70. In some embodiments, the substitution is at residue 88. In some embodiments, the substitution is at residue 89. In some embodiments, the substitution is at residue 90. In some embodiments, the substitution is at residue 91. In some embodiments, the substitution is at residue 93.

Cysteine substitution at a position within a domain or protein involves replacing an existing amino acid residue with a cysteine residue. Other examples of cysteine modifications can be found, for example, in US Publication No. 20170362301, which is incorporated herein by reference in its entirety. Alignment of sequences can be performed, for example, on the NCBI website using BlastP using default parameters.

In some embodiments, the FN3 domain that binds CD71 is internalized into the cell. In some embodiments, internalization of the FN3 domain may facilitate delivery of a detectable label or therapeutic agent into the cell. In some embodiments, internalization of the FN3 domain can facilitate delivery of cytotoxic agents into cells. Cytotoxic agents can act as therapeutic agents. In some embodiments, internalization of the FN3 domain can facilitate delivery into a cell of any of the detectable labels, therapeutics, and/or cytotoxic agents disclosed herein. In some embodiments, the cells are tumor cells. In some embodiments, the cells are liver cells. In some embodiments, the cells are muscle cells. In some embodiments, the cells are immune cells. In some embodiments, the cells are dendritic cells. In some embodiments, the cells are T-cells. In some embodiments, the cells are NK cells. In some embodiments, the cell is a B-cell. In some embodiments, the cells are cells of the central nervous system.

In some embodiments, the FN3 domain that binds CD71 is based on the Tencon sequence of SEQ ID NO: 276 or the Tencon 27 sequence of SEQ ID NO: 277, optionally at numbers 11, 14, 17, 37, 46, and 73. or has a substitution at residue position 86 (residue numbering corresponding to SEQ ID NO: 277).

SEQ ID NO: 276 = Original Tencon Sequence

SEQ ID NO: 277 = Stabilized Tencon (Tencon 27)

In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NOs: 1-7, 10, 12-219, 221-272, 292-299, or 304-306.

In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:1. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:2. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:3. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:4. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:5. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:6. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:7. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 10. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 12. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:13. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 14. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:15. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 16. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 17. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:18. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 19. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:20. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:21. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:22. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:23. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:24. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:25. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:26. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:27. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:28. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:29. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:30. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:31. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:32. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:33. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:34. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:35. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:36. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:37. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:38. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:39. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:40. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:41. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:42. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:43. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:44. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:45. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:46. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:47. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:48. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:49. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:50. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:51. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:52. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:53. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:54. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:55. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:56. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:57. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:58. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:59. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:60. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:61. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:62. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:63. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:64. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:65. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:66. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:67. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:68. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:69. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:70. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:71. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:72. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:73. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:74. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:75. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:76. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:77. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:78. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:79. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:80. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:81. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:82. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:83. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:84. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:85. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:86. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:87. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:88. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:89. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:90. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:91. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 92. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 93. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:94. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:95. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:96. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:97. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 98. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:99. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 100. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 101. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 102. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 103. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 104. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 105. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 106. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 107. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 108. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 109. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 110. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 111. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 112. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 113. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 114. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 115. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 116. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 117. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 118. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 119. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 120. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 121. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 122. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 123. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 124. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 125. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 126. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 127. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 128. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 129. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 130. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 131. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 132. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 133. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 134. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 135. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 136. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 137. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 138. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 139. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 140. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 141. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 142. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 143. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 144. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 145. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 146. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 147. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 148. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 149. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 150. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 151. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 152. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 153. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 154. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 155. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 156. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 157. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 158. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 159. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 160. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 161. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 162. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 163. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 164. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 165. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 166. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 167. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 168. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 169. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 170. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 171. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 172. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 173. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 174. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 175. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 176. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 177. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 178. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 179. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 180. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 181. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 182. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 183. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 184. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 185. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 186. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 187. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 188. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 189. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 190. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 191. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 192. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 193. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 194. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 195. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 196. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 197. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 198. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 199. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:200. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:201. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:202. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:203. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:204. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:205. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:206. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:207. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:208. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:209. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:210. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:211. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:212. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:213. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:214. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:215. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:216. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:217. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:218. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:219. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:221. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:222. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:223. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:224. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:225. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:226. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:227. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:228. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:229. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:230. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:231. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:232. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:233. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:234. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:235. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:236. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:237. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:238. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:239. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:240. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:241. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:242. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:243. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:244. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:245. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:246. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:247. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:248. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:249. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:250. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:251. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:252. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:253. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:254. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:255. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:256. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:257. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:258. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:259. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:260. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:261. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:262. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:263. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:264. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:265. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:266. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:267. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:268. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:269. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:270. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:271. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:272. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO:304. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 305. In some embodiments, the isolated FN3 domain that binds CD71 comprises the amino acid sequence of SEQ ID NO: 306.

In some embodiments, the FN3 domain binds human CD71 at a site on CD71 that does not compete with transferrin binding to CD71. In some embodiments, the FN3 domain comprises the sequence of SEQ ID NOs: 1-7, 10, 12-219, 221-272, 292-299, or 304-306.

In some embodiments, the isolated FN3 domain that binds CD71 comprises an initiator methionine (Met) linked to the N-terminus of the molecule.

Conjugates of FN3 domain binding to CD71 of the present disclosure

In some embodiments, an isolated FN3 domain that binds CD71 conjugated to heterologous molecule(s) is provided.

In some embodiments, the FN3 domain is conjugated to an oligonucleotide. For example, oligonucleotides can be used to inhibit the expression of genes or mRNA transcripts. Oligonucleotides may be siRNA, miRNA, antisense oligonucleotides, etc. Accordingly, in some embodiments, the FN3 domain may be conjugated to a polynucleotide such as, but not limited to, an siRNA molecule, an antisense molecule, an RNA molecule, or a DNA molecule. In some embodiments, the FN3 domain that binds CD71 is conjugated to an siRNA molecule using a linker as described herein. In some embodiments, the linker is a chemical linker.

In some embodiments, compositions comprising a polypeptide, such as a polypeptide comprising an FN3 domain linked to a nucleic acid molecule, are provided. Nucleic acid molecules may be, for example, siRNA molecules.

Accordingly, in some embodiments, siRNA is a double-stranded RNAi (dsRNA) agent that can inhibit expression of a target gene. The dsRNA agent includes a sense strand and an antisense strand. In some embodiments, each strand of the dsRNA agent may range from 12 to 40 nucleotides in length. For example, each strand may be 14 to 40 nucleotides long, 17 to 37 nucleotides long, 25 to 37 nucleotides long, 27 to 30 nucleotides long, 17 to 23 nucleotides long, 17 to 37 nucleotides long. 21 nucleotides in length, 17 to 19 nucleotides in length, 19 to 25 nucleotides in length, 19 to 23 nucleotides in length, 19 to 21 nucleotides in length, 21 to 25 nucleotides in length, or 21 to 23 nucleotides in length. It can be nucleotide length.

In some embodiments, the sense strand and antisense strand typically form a duplex dsRNA. The duplex region of a dsRNA agent may be 12 to 40 nucleotide pairs long. For example, duplex regions can be 14 to 40 nucleotide pairs long, 17 to 30 nucleotide pairs long, 25 to 35 nucleotide pairs long, 27 to 35 nucleotide pairs long, 17 to 23 nucleotide pairs long. Length, 17 to 21 nucleotide pairs long, 17 to 19 nucleotide pairs long, 19 to 25 nucleotide pairs long, 19 to 23 nucleotide pairs long, 19 to 21 nucleotide pairs long, 21 to 21 nucleotide pairs long. It may be 25 nucleotide pairs long or 21 to 23 nucleotide pairs long. In another example, duplex regions are 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, and 27 nucleotide pairs long. is selected from

In some embodiments, the dsRNA comprises one or more overhanging regions and/or capping groups of the dsRNA agent at the 3'-end or 5'-end or both ends of the strand. The overhang is 1 to 10 nucleotides long, 1 to 6 nucleotides long, for example 2 to 6 nucleotides long, 1 to 5 nucleotides long, 2 to 5 nucleotides long, 1 to 4 nucleotides long. 2 nucleotides in length, 2 to 4 nucleotides in length, 1 to 3 nucleotides in length, 2 to 3 nucleotides in length, or 1 to 2 nucleotides in length. Overhangs can occur when one strand is longer than the other, or when two strands of equal length are crossed. The overhang may form a mismatch with the target mRNA, or may be complementary to the gene sequence being targeted, or may be a different sequence. The first and second strands may also be joined by additional bases, for example, to form hairpins, or by other non-basic linkers.

In some embodiments, the nucleotides in the overhang region of the dsRNA agent are each independently 2-F 2'-Omethyl, thymidine (T), 2'-O-methoxyethyl-5-methyluridine (Teo), Including, but not limited to, 2'-sugar modifications such as 2'-O-methoxyethyladenosine (Aeo), 2'-O-methoxyethyl-5-methylcytidine (m5Ceo), and any combinations thereof. It may be a modified or unmodified nucleotide. For example, TT may be an overhang sequence on both ends of both strands. The overhang may form a mismatch with the target mRNA, or may be complementary to the gene sequence being targeted, or may be a different sequence.

The 5'-overhang or 3'-overhang of the sense strand, antisense strand, or both strands of the dsRNA agent may be phosphorylated. In some embodiments, the overhang region comprises two nucleotides with a phosphorothioate between the two nucleotides, where the two nucleotides may be the same or different. In one embodiment, the overhang is at the 3'-end of the sense strand, the antisense strand, or both strands. In one embodiment, this 3'-overhang is in the antisense strand. In one embodiment, this 3'-overhang is in the sense strand.

The dsRNA agonist may contain only a single overhang, which can enhance the interfering activity of the dsRNA without affecting its overall stability. For example, the single-strand overhang is located at the 3'-end of the sense strand or alternatively at the 3'-end of the antisense strand. The dsRNA may have blunt ends located at the 5'-end of the antisense strand (or 3'-end of the sense strand) or vice versa. Typically, the antisense strand of dsRNA has a nucleotide overhang at the 3'-end and the 5'-end is blunt. Without being bound by theory, the asymmetric blunt end at the 5'-end of the antisense strand and the 3'-end overhang of the antisense strand favor the guide strand loading in the RISC process. For example, a single overhang comprises at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 nucleotides in length.

In some embodiments, the dsRNA agent may also have two blunt ends at either end of the dsRNA duplex.

In some embodiments, all nucleotides of the sense and antisense strands of the dsRNA agent may be modified. Each nucleotide may have one or more modifications to one or both of the unlinked phosphate oxygens and/or one or more of the linked phosphate oxygens; Modification of the components of the ribose sugar, for example, two hydroxyls on the ribose sugar; Replacement of multiple phosphate moieties with a “Dephospho” linker; Modification or substitution of naturally occurring bases; and replacement or modification of the ribose-phosphate backbone.

In some embodiments, all or some of the bases of the 3' or 5' overhang may be modified, for example, with the modifications described herein. Modifications include, for example, modifications known in the art, such as modified deoxyribonucleotides, 2'-deoxy-2'-fluoro (2'-F), or It may include the use of modifications at the 2' position of the ribose sugar along with the use of 2'-O-methyl, and modifications of the phosphate group, such as phosphorothioate modifications. The overhang need not be homologous to the target sequence.

In some embodiments, each residue of the sense strand and antisense strand is independently LNA, HNA, CeNA, 2'-methoxyethyl, 2'-O-methyl, 2'-O-allyl, 2'-C-allyl, It is modified to 2'-deoxy or 2'-fluoro. A strand may contain more than one modification. In one embodiment, each residue of the sense strand and antisense strand is independently modified 2'-O-methyl or 2'-fluoro.

In some embodiments, at least two different modifications are typically present in the sense strand and the antisense strand. These two modifications can be 2'-deoxy, 2'-O-methyl or 2'-fluoro modifications, acyclic nucleotides, etc.

In one embodiment, the sense strand and antisense strand each comprise two differently modified nucleotides selected from 2'-fluoro, 2'-O-methyl, or 2'-deoxy.

The dsRNA agent may further comprise at least one phosphorothioate or methylphosphonate internucleotide linkage. Phosphorothioate or methylphosphonate internucleotide linkage modifications can occur both at any nucleotide in the sense or antisense strand or at any position on the strand. For example, internucleotide linkage modifications may occur at any nucleotide in the sense strand and/or antisense strand; Each internucleotide linkage modification can occur in an alternating pattern in either the sense strand or the antisense strand; Alternatively, either the sense strand or the antisense strand comprises both an alternating pattern of internucleotide linkage modifications. The alternating pattern of inter-nucleotide linkage modifications of the sense strand may be the same or different from that of the antisense strand, and the alternating pattern of inter-nucleotide linkage modifications of the sense strand may shift compared to the alternating pattern of inter-nucleotide linkage modifications of the antisense strand. You can have it.

In some embodiments, the dsRNA agent comprises a phosphorothioate or methylphosphonate internucleotide linkage modification in the overhang region. For example, the overhang region includes two nucleotides with a phosphorothioate or methylphosphonate internucleotide linkage between the two nucleotides. Internucleotide linkage modifications may also be made to link overhanging nucleotides with paired terminal nucleotides within the duplex region. For example, at least two, three, four, or all of the overhang nucleotides may be linked via phosphorothioate or methylphosphonate internucleotide linkages, and optionally, the overhang nucleotides may be linked by linking the overhang nucleotides with a pair flanking the overhang nucleotides. There may be additional phosphorothioate or methylphosphonate internucleotide linkages linking these nucleotides. For example, there may be at least two phosphorothioate internucleotide linkages between the three terminal nucleotides, where two of the three nucleotides are overhanging nucleotides and the third is a paired nucleotide next to the overhanging nucleotide. am. In some embodiments, these terminal three nucleotides may be at the 3'-end of the antisense strand.

In some embodiments, the dsRNA composition is linked by modified bases or nucleoside analogs as described in U.S. Pat. No. 7,427,672, which is incorporated herein by reference.

In some embodiments, a linker can be used to connect the FN3 domain as described herein to the sense strand having Formula I:

.

In some embodiments, a linker can be used to connect the FN3 domain as described herein to the antisense strand having Formula II:

where X _AS represents the antisense strand and F ₁ represents the FN3 domain as described herein.

In some embodiments, the linker is covalently attached to F1 via a cysteine residue present in F1, which can be illustrated as follows:

.

In some embodiments, the linked ds RNA and FN3 domain as described herein have Formula III:

wherein C1 represents the same or different FN3 domain as described herein.

In some embodiments, A1-B1 has the formula:

wherein F ₁ is a polypeptide _comprising at least one FN3 domain _, conjugated to L _{1 ,} and L ₁ is linked to is the sense strand, and X _AS is the 3' to 5' oligonucleotide antisense strand of the double-stranded siRNA molecule; X _S and X _AS form a double-stranded siRNA molecule.

The structure of the additional linker is as follows:

mal-C ₂ H ₄ C(O)(NH)-(CH ₂ ) ₆ - is ego;

(Mal-(PEG) ₁₂ )(NH)CH ₂ ) ₆ ) is

ego;

Mal-NH-(CH ₂ ) ₆ -, which can also be referred to as aminohexyl linker-(CH ₂ ) ₆ - ego; and

Val-Cit Paba It has a structure.

As described herein, in some embodiments, a nucleic acid molecule can be modified to include a linker at the 5' end of the sense strand of the dsRNA. In some embodiments, the nucleic acid molecule can be modified to include a vinyl phosphonate at the 5' end of the antisense strand of the dsRNA. In some embodiments, the nucleic acid molecule can be modified to include a linker at the 3' end of the sense strand of the dsRNA. In some embodiments, the nucleic acid molecule can be modified to include a vinyl phosphonate at the 3' end of the antisense strand of the dsRNA. A linker can be used to connect dsRNA to the FN3 domain. The linker may, for example, be covalent to a cysteine residue on the FN3 domain that is naturally present or substituted as described herein and, e.g., in U.S. Pat. No. 10,196,446, which is incorporated herein by reference in its entirety. It can be attached.

In some embodiments, the peptide is conjugated to a lipid nanoparticle, which can be used, for example, for cell-specific targeting.

In some embodiments, the protein is conjugated to a binding moiety that targets CD71 or another protein for protein degradation. For example, proteins can be conjugated to PROTACS (binding moieties for E3 ubiquitin ligase) to transfer the protein to the E3 ligase. They may be connected through a linker such as a glycine-serine linker, etc.

The FN3 domain that binds CD71 may also be conjugated or linked to another FN3 domain that binds a different target other than CD71. This may allow the peptide to be multispecific (e.g., bispecific, trispecific, etc.) and bind to CD71 and another, e.g., protein. In some embodiments, the CD71 FN3 binding domain is linked to another FN3 domain that binds to an antigen expressed by tumor cells (tumor antigen).

In some embodiments, FN3 domains can be linked together by a linker to form a bivalent FN3 domain. The linker may be a flexible linker. In some embodiments, the linker is a G/S linker. In some embodiments, the linker has 1, 2, 3, or 4 G/S repeats. The G/S repeat unit is four glycines followed by a serine, e.g. GGGGS (SEQ ID NO: 308). In some embodiments, the FN3 domains comprising two FN3 domains are connected by a linker as provided herein. Exemplary linkers include (GS)2 (SEQ ID NO: 278), (GGGS)2 (SEQ ID NO: 279), (GGGGS)1-5 (SEQ ID NO: 280), (AP)1-20 (SEQ ID NO: 311); (AP)2 (SEQ ID NO: 281), (AP)5 (SEQ ID NO: 282), (AP)10 (SEQ ID NO: 283), (AP)20 (SEQ ID NO: 284), A(EAAAK)5AAA (SEQ ID NO: 285) or (EAAAK)1-5 (SEQ ID NO: 307). In some embodiments, the linker is EAAAKEAAAAKEAAAAKEAAAK (SEQ ID NO: 300); GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 301); APAPAPAPAP (SEQ ID NO: 302); Or it is or includes the amino acid sequence of EAAAK (SEQ ID NO: 303).

In some embodiments, the xenogeneic molecule is a detectable label or therapeutic agent such as, but not limited to, a cytotoxic agent.

In some embodiments, an FN3 domain that binds CD71 conjugated to a detectable label is provided. Non-limiting examples of labels are provided herein.

In some embodiments, an FN3 domain that binds CD71 conjugated to a therapeutic agent is provided. Non-limiting examples of therapeutic agents such as, but not limited to, cytotoxic agents are provided herein.

FN3 domain binding to CD71 conjugated to a detectable label in vivo Or it can be used to assess the expression of CD71 in samples such as tumor tissue in vitro. The FN3 domain bound to CD71 conjugated to a detectable label can be used to assess the expression of CD71 in sample blood, immune cells, or dendritic cells in vivo or in vitro.

Detectable labels include compositions that render CD71 detectable via spectroscopic, photochemical, biochemical, immunochemical or other chemical methods when conjugated to the FN3 domain that binds to CD71.

Exemplary detectable labels include radioactive isotopes, magnetic beads, metal beads, colloidal particles, fluorescent dyes, electron-dense reagents, enzymes (e.g., commonly used in ELISA), biotin, digoxigenin, haptens, luminescence. Molecules, chemiluminescent molecules, fluorochromes, fluorophores, fluorescence quenchers, colored molecules, radioisotopes, scintillants, avidin, streptavidin, protein A, protein G, antibodies or fragments thereof, polyhistidine, Ni2+, fragments Includes, but is not limited to, tags, myc tags, heavy metals, enzymes, alkaline phosphatase, peroxidase, luciferase, electron donor/acceptor, acridinium ester, and colorimetric substrates.

A detectable label may spontaneously emit a signal, such as when the detectable label is a radioactive isotope. In some embodiments, the detectable label emits a signal as a result of stimulation by an external stimulus, such as a magnetic or electric field.

Exemplary radioisotopes may be γ-emitting, Auger-emitting, β-emitting, alpha-emitting or positron-emitting radioisotopes. Exemplary radioisotopes include 3H, 11C, 13C, 15N, 18F, 19F, 55CO, 57CO, 60CO, 61CU, 62CU, 64CU, 67CU, 68GA, 72AS, 75BR, 86Y, 89ZR, 90SR, 94MTC Includes 1231, 1241, 125I, 1311, 211At, 212Bi, 213Bi, 223Ra, 226Ra, 225Ac and 227Ac.

Exemplary metal atoms include calcium atom, scandium atom, titanium atom, vanadium atom, chromium atom, manganese atom, iron atom, cobalt atom, nickel atom, copper atom, zinc atom, gallium atom, germanium atom, arsenic atom, selenium. Atom, bromine atom, krypton atom, rubidium atom, strontium atom, yttrium atom, zirconium atom, niobium atom, molybdenum atom, technetium atom, ruthenium atom, rhodium atom, palladium atom, silver atom, cadmium atom, indium atom, tin atom , antimony atom, tellurium atom, iodine atom, xenon atom, cesium atom, barium atom, lanthanum atom, hafnium atom, tantalum atom, tungsten atom, rhenium atom, osmium atom, iridium atom, platinum atom, gold atom, mercury. Atom, thallium atom, lead atom, bismuth atom, francium atom, radium atom, actinium atom, cerium atom, praseodymium atom, neodymium atom, promethium atom, samarium atom, europium atom, gadolinium atom, terbium atom, dysprosium atom, holmium atom. , erbium atom, tholium atom, ytterbium atom, lutetium atom, thorium atom, protactinium atom, uranium atom, neptunium atom, plutonium atom, americium atom, curium atom, berkelium atom, californium atom, einsitinium atom, fermium atom, mendelevium atom. , is a metal with an atomic number greater than 20, such as a nobelium atom or a lawrencium atom.

In some embodiments, the metal atom may be an alkaline earth metal with an atomic number greater than 20.

In some embodiments, the metal atom may be lanthanide.

In some embodiments, the metal atom can be an actinide.

In some embodiments, the metal atom can be a transition metal.

In some embodiments, the metal atom may be a poor metal.

In some embodiments, the metal atoms can be gold atoms, bismuth atoms, tantalum atoms, and gadolinium atoms.

In some embodiments, the metal atom may be a metal with atomic number 53 (i.e., iodine) to 83 (i.e., bismuth).

In some embodiments, the metal atom may be an atom suitable for magnetic resonance imaging.

Metal atoms are Ba2+, Bi3+, Cs+, Ca2+, Cr2+, Cr3+, Cr6+, Co2+, Co3+, Cu+, Cu2+, Cu3+, Ga3+, Gd3+, Au+, Au3+, Fe2+, Fe3+, F3+, Pb2+, Mn2+, Mn3+, Mn4+, Mn7+. , can be metal ions in the form of +1, +2 or +3 oxidation states such as Hg2+, Ni2+, Ni3+, Ag+, Sr2+, Sn2+, Sn4+ and Zn2+. The metal atoms may include metal oxides such as iron oxide, manganese oxide, or gadolinium oxide.

Suitable dyes include any commercially available dye, such as, for example, 5(6)-carboxyfluorescein, IRDye 680RD maleimide or IRDye 800CW, ruthenium polypyridyl dye, etc.

Suitable fluorophores include fluorescein isothiocyanate (FITC), fluorescein thiosemicarbazide, rhodamine, Texas Red, CyDye (e.g. Cy3, Cy5, Cy5.5), Alexa Fluor (e.g. For example, Alexa488, Alexa555, Alexa594; Alexa647), near-infrared (NIR) (700 nm to 900 nm) fluorescent dyes, and carbocyanine and aminostyryl dyes.

The FN3 domain, which specifically binds to CD71 conjugated to a detectable label, can be used as an imaging agent, for example, to diagnose tumor distribution, the presence of tumor cells, and/or to assess tumor recurrence. The FN3 domain, which specifically binds to CD71 conjugated to a detectable label, can be used on a variety of cells in the body, including, for example, dendritic cells, T-cells, NK cells, B-cell immune cells, muscle cells, and cells of the central nervous system. It can be used as an imaging agent to assess the presence of CD71 positive cells in tissues.

In some embodiments, the FN3 domain that specifically binds to CD71 is conjugated to a therapeutic agent such as, but not limited to, a cytotoxic agent.

In some embodiments, the therapeutic agent is a chemotherapeutic agent, drug, growth inhibitor, toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin or fragments thereof), or a radioactive isotope (i.e., radioconjugate). )am.

The FN3 domain that binds to CD71 conjugated to a therapeutic agent disclosed herein may provide a therapeutic agent for CD71 expressing cells (e.g., tumor cells, dendritic cells, T-cells, NK cells, B-cell immune cells, cells of the central nervous system). It can be used for targeted delivery and intracellular accumulation. Without wishing to be bound by any particular theory, this type of delivery may be helpful in cases where systemic administration of such unconjugated agents may result in unacceptable levels of toxicity to normal cells.

In some embodiments, the therapeutic agent is cytotoxic and/or cytotoxic by mechanisms such as, but not limited to, tubulin binding, DNA binding, topoisomerase inhibition, DNA cross-linking, chelation, spliceosome inhibition, NAMPT inhibition, and HDAC inhibition. It may cause cytostatic effects.

In some embodiments, the therapeutic agent is a spliceosome inhibitor, NAMPT inhibitor, or HDAC inhibitor. In some embodiments, the agent is an immune system agonist, such as TLR7,8,9, RIG-I (dsRNA), and STING (CpG) agonist. In some embodiments, the agent is daunomycin, doxorubicin, methotrexate, vindesine, a bacterial toxin such as diphtheria toxin, ricin, geldanamycin, a maytansinoid, or calicheamicin.

In some embodiments, the therapeutic agent is diphtheria A chain, unbound active fragment of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa ), ricin A chain, abrin A chain, modecin A chain, alpha -sarcin, Aleurites fordii protein, dianthin protein, Phytolaca americana protein (PAPI, PAPII and PAP-S), momordica charantia inhibitor, cursin, Enzymatically active toxins such as crotin, sapaonaria officinalis inhibitors, gelonin, mitogellin, restrictosin, phenomycin, enomycin or trichothecene.

In some embodiments, the therapeutic agent is a radioisotope such as 212Bi, 131I, 131In, 90Y, or 186Re.

In some embodiments, the therapeutic agent is dolastatin or dolostatin peptide analogs and derivatives, auristatin or monomethyl auristatin phenylalanine. Exemplary molecules are disclosed in US Pat. Nos. 5,635,483 and 5,780,588. Dolastatin and auristatin interfere with microtubule dynamics, GTP hydrolysis, and nuclear and cell division (5,780,588) and have been shown to have anticancer and antifungal activities. The dolastatin or auristatin drug moiety may be attached to the FN3 domain via the N (amino) or C (carboxyl) terminus of the peptide drug moiety (WO 02/088172) or via any cysteine engineered into the FN3 domain. You can.

In some embodiments, the therapeutic agent is, for example, auristatin, camptothecin, duocamycin, etoposide, maytansine and maytansinoids, taxanes, benzodiazepines, or benzodiazepine-containing drugs (e.g. For example, it may be a pyrrolo[1,41-benzodiazepine (PBD), indolinobenzodiazepine and oxazolidinobenzodiazepine) or vinca alkaloid.

The FN3 domain that specifically binds to CD71 can be conjugated to a detectable label using known methods.

In some embodiments, the detectable label is complexed with a chelating agent.

In some embodiments, the detectable label is conjugated to the FN3 domain that binds CD71 via a linker as described above.

Detectable labels, therapeutic compounds or cytotoxic compounds can be linked directly or indirectly to the FN3 domain that binds CD71 using known methods. Suitable linkers are known in the art and include, for example, prosthetic groups, biphenolic linkers (N-succinimidyl-benzoate; derivatives of dodecaborate), chelating moieties of both macrocyclic and acyclic chelating agents. Ti, such as 1,4,7,10-tetraazacyclododecane-1,4,7,10, a derivative of tetraacetic acid (DOTA), a derivative of diethylenetriaminepentaacetic acid (DTPA), S-2- Derivatives of (4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and 1,4,8,11-tetraazacyclodosedane Derivatives of -1,4,8,11-tetraacetic acid (TETA), N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane (IT), imidoester (e.g. dimethyl adipimidate HCl), bifunctional derivatives of active esters (e.g. disuccinimidyl suberate), aldehydes (e.g. glutaraldehyde), bis-azido compounds (e.g. zidobenzoyl)hexanediamine), bis-diazonium derivatives (e.g., bis(p-diazoniumbenzoyl)ethylenediamine), diisocyanates (e.g., toluene 2,6-diisocyanate), and bis-active fluorine compounds (e.g., 1,5-difluoro-2,4-dinitrobenzene) and other chelating moieties. Suitable peptide linkers are well known.

In some embodiments, the FN3 domain that binds CD71 is removed from the blood via renal elimination.

From a library based on Tencon sequences Isolation of CD71 binding FN3 domain

Tencon (SEQ ID NO: 276) is a non-naturally occurring fibronectin type III (FN3) domain designed from the consensus sequence of 15 FN3 domains from human tenascin-C (Jacobs et al., Protein Engineering, Design, and Selection, 25:107-117, 2012; US Publication No. 2010/0216708). The crystal structure of Tencon shows six surface-exposed loops connecting the seven beta-strands characteristic of the FN3 domain, designated A, B, C, D, E, F and G; The loops are referred to as AB, BC, CD, DE, EF and FG loops (Bork and Doolittle, Proc Natl Acad Sci USA 89:8990-8992, 1992; US Pat. No. 6,673,901). These loops or selected residues within each loop can be randomized to build a library of fibronectin type III (FN3) domains that can be used to select new molecules that bind CD71. Table 1 shows the location and sequence of each loop and beta-strand of Tencon (SEQ ID NO: 276).

Accordingly, libraries designed based on Tencon sequences may have randomized FG loops or randomized BC and FG loops, such as libraries TCL1 or TCL2 as described below. The Tencon BC loop is 7 amino acids long, so 1, 2, 3, 4, 5, 6 or 7 amino acids can be randomized in the diversified library in the BC loop and designed based on the Tencon sequence. You can. Since the Tencon FG loop is 7 amino acids long, 1, 2, 3, 4, 5, 6 or 7 amino acids can be randomized in the diversified library in the FG loop and designed based on the Tencon sequence. You can. Additional diversity in the loops in the Tencon library can be achieved by insertion and/or deletion of residues in the loop. For example, the FG and/or BC loops can be extended by 1 to 22 amino acids or shortened by 1 to 3 amino acids. The FG loop of Tencon is 7 amino acids long, whereas the corresponding loop of an antibody heavy chain ranges from 4 to 28 residues. To provide maximum diversity, FG loops can be varied in sequence as well as length to correspond to the antibody CDR3 length range of 4 to 28 residues. For example, the FG loop can be further varied in length by extending the loop by an additional 1, 2, 3, 4, or 5 amino acids.

Libraries designed based on the Tencon sequence may also have randomized surrogate surfaces that flank the FN3 domain and include two or more beta strands and at least one loop. One of these alternative surfaces is formed by the amino acids of the C and F beta-strands and the CD and FG loops (C-CD-F-FG surface). A library designed based on the Tencon alternative C-CD-F-FG surface is described in US Publication No. 2013/0226834. Libraries designed based on the Tencon sequence also include Tencon variants such as Tencon variants with substitutions at residue positions 11, 14, 17, 37, 46, 73, or 86 (residue numbering corresponding to SEQ ID NO: 276). Includes a library designed based on variants, which have been shown to improve thermal stability. Exemplary Tencon variants are described in US Publication No. 2011/0274623 and include Tencon 27 (SEQ ID NO: 277), which has the substitutions E11R, L17A, N46V and E86I when compared to Tencon in SEQ ID NO: 276.

Tencon and other FN3 sequence-based libraries can be randomized at selected residue positions using random or defined sets of amino acids. For example, in a library with random substitutions, variants can be generated using the NNK codon, which encodes all 20 naturally occurring amino acids. In various other schemes, the DVK codon can be used to encode the amino acids Ala, Trp, Tyr, Lys, Thr, Asn, Lys, Ser, Arg, Asp, Glu, Gly and Cys. Alternatively, the NNS codon can be used to generate all 20 amino acid residues and simultaneously reduce the frequency of stop codons. Libraries of FN3 domains with biased amino acid distributions at the positions to be diversified can be synthesized, for example, using Slonomics® technology (http://www_sloning_com). The technology uses pre-made double-stranded triplet libraries that serve as sufficient universal building blocks during the synthesis of thousands of genes. A triplet library represents all possible sequence combinations necessary to construct any desired DNA molecule. Codon designations follow the well-known IUB code.

The FN3 domain, which specifically binds to CD71, generates FN3 libraries, such as the Tencon library, that use cis display to ligate DNA fragments encoding the scaffold protein to DNA fragments encoding RepA, forming the protein after in vitro translation. Generating a pool of DNA complexes, where each protein is stably associated with the DNA that encodes it (U.S. Pat. No. 7,842,476; Odegrip et al., Proc Natl Acad Sci USA 101, 2806-2810, 2004), Isolation can be achieved by assaying the library for specific binding to PSMA by any method known in the art and described in the Examples. Exemplary well-known methods that may be used are ELISA, sandwich immunoassays, and competitive and non-competitive assays (e.g., Ausubel et al., eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons , Inc., New York]). Identified FN3 domains that specifically bind CD71 are further characterized for binding to CD71, regulation of CD71 activity, internalization, stability and other desired properties.

The FN3 domain that specifically binds to CD71 can be generated by generating a library using any FN3 domain as a template and screening the library for molecules that specifically bind to CD71 using the method provided therein. Exemplary FN3 domains that can be used are the 3rd FN3 domain of tenascin C (TN3), Fibcon, and the 10th FN3 domain of fibronectin (FN10). Accordingly, PCT applications WO 2010/051274, WO 2011/137319 and WO 2013/049275 are incorporated herein in their entirety. Standard cloning and expression techniques are used to clone the clone library into a vector or synthesize a double-stranded cDNA cassette of the library and express or translate the library in vitro. For example, ribosome display (Hanes and Pluckthun, Proc Natl Acad Sci USA; 94, 4937-4942, 1997), mRNA display (Roberts and Szostak , Proc Natl Acad Sci USA, 94, 12297-12302, 1997) or other cell-free systems (US Pat. No. 5,643,768) can be used. Libraries of FN3 domain variants can be expressed, for example, as fusion proteins displayed on the surface of any suitable bacteriophage. Methods for displaying fusion polypeptides on the surface of bacteriophages are well known (US Publication No. 2011/0118144; International Publication No. WO2009/085462; US Patent No. 6,969,108; US Patent No. 6,172,197; US Patent No. 5,223,409; US Patent No. 6,582,915; US Patent No. 6,472,147).

In some embodiments, the FN3 domain that binds CD71 has the Tencon sequence of SEQ ID NO: 276, optionally with substitutions at residues at positions 11, 14, 17, 37, 46, 73, and/or 86. or based on the Tencon 27 sequence of SEQ ID NO: 277, SEQ ID NO: 276, or SEQ ID NO: 277.

In some embodiments, the FN3 protein or polypeptide binds human CD71 at a site on CD71 that does not compete with transferrin binding to CD71. As used herein, a region of CD71 that does not compete with transferrin binding to CD71 refers to an epitope or portion of CD71 for which the binding of FN3 protein does not compete with or inhibit the binding of transferrin to CD71. Competition or lack thereof may be complete or partial. In some embodiments, binding also does not inhibit internalization of transferrin into cells through interaction with CD71.

In some embodiments, methods are provided for identifying FN3 protein that binds CD71 at a site that does not compete with or inhibit transferrin binding to CD71. In some embodiments, the method comprises contacting CD71 with a test FN3 protein in the presence of transferrin or an agent that binds to the CD71 transferrin binding site; and identifying the test FN3 protein that binds to CD71 in the presence of the test transferrin or an agent that binds to the CD71 transferrin binding site. In some embodiments, the method comprises isolating a test FN3 protein that binds CD71 in the presence of transferrin or an agent that binds to the CD71 transferrin binding site. In some embodiments, the method includes sequencing a test FN3 protein that binds to CD71 in the presence of transferrin or an agent that binds to the CD71 transferrin binding site. In some embodiments, the method comprises preparing or obtaining a nucleic acid sequence encoding a test FN3 protein that binds CD71 in the presence of transferrin or an agent that binds to the CD71 transferrin binding site. In some embodiments, the method comprises a test method that binds CD71 in the presence of transferrin or an agent that binds a CD71 transferrin binding site from a nucleic acid sequence encoding a test FN3 protein that binds to CD71 in the presence of transferrin or an agent that binds a CD71 transferrin binding site. and expressing the test FN3 protein. In some embodiments, the test FN3 protein is expressed in the cell. In some embodiments, the method includes isolating and/or purifying the expressed test FN3 protein.

In some embodiments, an FN3 protein is provided, wherein the FN3 protein is identified according to any of the methods provided herein.

The FN3 domain that specifically binds to CD71 can be modified to improve properties such as improving thermal stability and reversibility of thermal folding and unfolding. To increase the apparent thermal stability of proteins and enzymes, design of highly similar thermostability sequences, stabilizing disulfide bridges, mutations that increase alpha-helix propensity, manipulation of salt bridges, alteration of the surface charge of proteins, directed evolution, and Several methods have been applied, including rational design based on comparison with the composition of the consensus sequence (Lehmann and Wyss, Curr. Opin. Biotechnol., 12, 371-375, 2001). High thermal stability can increase the yield of expressed protein, improve solubility or activity, reduce immunogenicity, and minimize the need for cold chain during manufacturing. Residues that can be substituted to improve the thermal stability of Tencon (SEQ ID NO: 276) are residue positions 11, 14, 17, 37, 46, 73, or 86, which are disclosed in US Publication No. 2011/0274623 It is described in no. Substitutions corresponding to these residues can be incorporated into FN3 domains comprising the molecules disclosed herein.

Measurements of protein stability and protein instability can be viewed as the same or different aspects of protein integrity. Proteins are exposed to heat, ultraviolet or ionizing radiation, changes in ambient osmotic pressure and, in the case of liquid solutions, pH, mechanical shear forces due to small pore-size filtration, ultraviolet radiation, ionizing radiation such as that by gamma irradiation, chemical or thermal dehydration or destruction of the protein structure. susceptible to degeneration or "unstable" caused by any other action or force that may cause The stability of a molecule can be determined using standard methods. For example, the stability of a molecule can be determined by measuring the thermal melting (“T _m ”) temperature, i.e., the temperature in degrees Celsius at which half of the molecule unfolds, using standard methods. Typically, the higher the T _m, the more stable the molecule. In addition to heat, the chemical environment also changes a protein's ability to maintain a specific three-dimensional structure.

In some embodiments, the FN3 domain that binds CD71 binds at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% compared to the same domain before manipulation as measured by an increase in Tm. %, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% or more.

Chemical denaturation can likewise be measured by a variety of methods. Chemical denaturants include guanidinium hydrochloride, guanidinium thiocyanate, urea, acetone, organic solvents (DMF, benzene, acetonitrile), salts (ammonium sulfate, lithium bromide, lithium chloride, sodium bromide, calcium chloride, sodium chloride); Reducing agents (e.g. dithiothreitol, beta-mercaptoethanol, dinitrothiobenzene and hydrides such as sodium borohydride), nonionic and ionic detergents, acids (e.g. hydrochloric acid (HCl)) ), acetic acid (CH ₃ COOH), halogenated acetic acid), hydrophobic molecules (e.g., phospholipids), and targeted denaturants. Quantification of the degree of denaturation may depend on physicochemical properties such as loss of functional properties such as the ability to bind target molecules or a tendency for aggregation, exposure of residues previously inaccessible to solvents, or destruction or formation of disulfide bonds. .

The FN3 domain that binds CD71 can be used to create a bi- or multispecific scaffold that binds two or more different target molecules simultaneously, e.g. as a means to increase the valence of target molecule binding and thus increase avidity. , can be produced as dimers or multimers. Dimers and multimers are formed by linking monospecific, bi- or multispecific protein scaffolds, for example, by including amino acid linkers, such as linkers comprising poly-glycine, glycine and serine or alanine and proline. can be created. Exemplary linkers include (GS)2 (SEQ ID NO: 278), (GGGS)2 (SEQ ID NO: 279), (GGGGS)1-5 (SEQ ID NO: 280), (AP)1-20 (SEQ ID NO: 311); (AP)2 (SEQ ID NO: 281), (AP)5 (SEQ ID NO: 282), (AP)10 (SEQ ID NO: 283), (AP)20 (SEQ ID NO: 284), A(EAAAK)5AAA (SEQ ID NO: 285) or (EAAAK)1-5 (SEQ ID NO: 307). In some embodiments, the linker is EAAAKEAAAAKEAAAAKEAAAK (SEQ ID NO: 300); GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 301); APAPAPAPAP (SEQ ID NO: 302); or the amino acid sequence of EAAAK (SEQ ID NO: 303).

Dimers and multimers can be linked to each other in the N to C direction. Naturally occurring linkers as well as artificial peptide linkers for linking polypeptides into novel linked fusion polypeptides are well known in the literature (Hallewell et al., J Biol Chem 264, 5260-5268, 1989; Alfthan et al., Protein Eng. 8, 725-731, 1995; Robinson & Sauer, Biochemistry 35, 109-116, 1996; US Patent No. 5,856,456).

Half-life extending moiety

The FN3 domain that specifically binds CD71 can incorporate other subunits, for example, through covalent interactions. In some embodiments, the FN3 domain that specifically binds CD71 further comprises a half-life extending moiety. Exemplary half-life extending moieties are albumin, albumin variants, albumin-binding proteins and/or domains, transferrin, and fragments and analogs thereof, and Fc regions. The amino acid sequence of the human Fc region is well known and includes the IgG1, IgG2, IgG3, IgG4, IgM, IgA and IgE Fc regions. In some embodiments, the FN3 domain that specifically binds to CD71 may incorporate a second FN3 domain that binds to a molecule that extends the half-life of the entire molecule, such as, but not limited to, any of the half-life extending moieties described herein. there is. In some embodiments, the second FN3 domain binds albumin, albumin variants, albumin-binding proteins and/or domains and fragments and analogs thereof.

All or part of the antibody constant region may exhibit antibody-like properties, particularly C1q binding, complement dependent cytotoxicity (CDC), Fc receptor binding, and antibody-dependent cell-mediated cytotoxicity. :ADCC), phagocytosis, and Fc effector functions such as downregulation of cell surface receptors (e.g., B cell receptor; BCR). and can be further modified by modifying the Fc residue responsible for this activity (for review; see Strohl, Curr Opin Biotechnol. 20, 685-691, 2009).

For the desired properties, polyethylene glycol (PEG) molecules, such as PEG5000 or PEG20,000, fatty acids and fatty acid esters of various chain lengths, such as laurate, myristate, stearate, arachidate, behenate, oleate. , arachidonate, octanedioic acid, tetradecanedioic acid, octadecanedioic acid, docosanedioic acid, etc., polylysine, octane, additional moieties such as carbohydrates (dextran, cellulose, oligo- or polysaccharides). Ti can be incorporated into the FN3 domain, which specifically binds to CD71. These moieties can be fused directly to protein scaffold coding sequences and generated by standard cloning and expression techniques. Alternatively, well-known chemical coupling methods can be used to attach moieties to the recombinantly produced molecules disclosed herein.

The pegyl moiety can be created by, for example, incorporating a cysteine residue into the C-terminus of the molecule or by manipulating the cysteine into a residue position that points away from the binding side of the molecule and attaching the pegyl group to the cysteine using well-known methods. It can be added to the FN3 domain, which binds to CD71 by attaching to it.

FN3 domains that specifically bind CD71 incorporating additional moieties can be compared for functionality by several well-known assays. For example, altered properties due to incorporation of the Fc domain and/or Fc domain variants can be measured using soluble forms of the receptor, such as FcγRI, FcγRII, FcγRIII or FcRn receptors, or by measuring, for example, ADCC or CDC, or in vivo. In my model, the pharmacokinetic properties of the molecules disclosed herein can be assayed in an Fc receptor binding assay using well-known cell-based assays.

Polynucleotides, vectors, host cells

In some embodiments, a nucleic acid encoding a FN3 domain that specifically binds to CD71, prokaryotic, as part of an isolated polynucleotide or expression vector or as part of a linear DNA sequence comprising a linear DNA sequence used for in vitro transcription/translation. Vectors are provided that are compatible with biological, eukaryotic or filamentous phage expression, secretion and/or compositions thereof or display of directed mutagenic factors. Although certain exemplary polynucleotides are disclosed herein, given the degeneracy of the genetic code or codon preferences in a given expression system, other polynucleotides encoding the FN3 domains disclosed herein are also within the scope of the disclosure. .

In some embodiments, the isolated polynucleotide encodes an FN3 domain that specifically binds to CD71 comprising the amino acid sequence of SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306. do.

The polynucleotides disclosed herein are produced by chemical synthesis, such as solid-phase polynucleotide synthesis in an automated polynucleotide synthesizer, and can be assembled into complete single- or double-stranded molecules. Alternatively, polynucleotides disclosed herein may be produced by other techniques, such as PCR followed by routine cloning. Techniques for producing or obtaining polynucleotides of a given known sequence are well known in the art.

The polynucleotides disclosed herein may include at least one non-coding sequence, such as a promoter or enhancer sequence, an intron, a polyadenylation signal, a cis sequence that facilitates RepA binding, etc. The polynucleotide sequence may also contain, for example, additional sequences encoding additional amino acids, a signal sequence, RepA, Fc, etc., encoding a marker or a tag sequence such as a histidine tag or an HA tag to facilitate purification or detection of the protein. It may include a fusion protein partner or a bacteriophage coating protein such as pIX or pIII.

In some embodiments, vectors comprising at least one polynucleotide disclosed herein are provided. Such vectors may be plasmid vectors, viral vectors, vectors for baculovirus expression, transposon-based vectors, or any other vector suitable for introducing the polynucleotides disclosed herein into a given organism or genetic background by any means. there is. Such vectors may be expression vectors containing nucleic acid sequence elements capable of controlling, regulating, causing or allowing expression of the polypeptide encoded by such vector. These elements may include transcription enhancer binding sites, RNA polymerase initiation sites, ribosome binding sites, and other sites that facilitate expression of the encoded polypeptide in a given expression system. These expression systems can be cell-based or cell-free systems well known in the art.

In some embodiments, a host cell containing a vector is provided. The FN3 domain that specifically binds to CD71 can optionally be produced by a cell line, mixed cell line, immortalized cell, or clonal population of immortalized cells, as well known in the art. See, for example, Ausubel, et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., NY, NY (1987-2001); Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor, NY (1989); Harlow and Lane, Antibodies, a Laboratory Manual, Cold Spring Harbor, NY (1989); Colligan, et al., eds., Current Protocols in Immunology, John Wiley & Sons, Inc., NY (1994-2001); See Colligan et al., Current Protocols in Protein Science, John Wiley & Sons, NY, NY, (1997-2001).

Host cells selected for expression may be of mammalian origin or may be of COS-1, COS-7, HEK293, BHK21, CHO, BSC-1, He G2, SP2/0, HeLa, myeloma, lymphoma, yeast, insect or plant. Cells or any derivative thereof, immortalized or transformed cells. Alternatively, the host cell may be a species or organism that is unable to glycosylate the polypeptide, such as BL21, BL21(DE3), BL21-GOLD(DE3), XL1-Blue, JM109, HMS174, HMS174(DE3) and The same prokaryotic cell or organism and any natural or engineered strain of Escherichia coli, Klebsiella spp., or Pseudomonas spp.

In some embodiments, a method of producing an isolated FN3 domain that binds CD71 includes culturing the isolated host cell under conditions that allow expression of the isolated FN3 domain that binds CD71 and purifying the FN3 domain. .

The FN3 domain that binds to CD71 is subjected to well-known methods, such as protein A purification, ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, and affinity chromatography. It can be purified from recombinant cell culture by chromatography, hydroxyapatite chromatography and lectin chromatography or high performance liquid chromatography (HPLC).

In some embodiments, the FN3 domain that specifically binds to CD71 comprises the amino acid sequence of SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306, wherein the histidine tag is For ease of use, it was attached to the N- or C-terminus of the polypeptide. In some embodiments, the histidine tag (His-tag) includes 6 histidine residues (SEQ ID NO: 309). In a further embodiment, the His-tag is connected to the FN3 domain by at least one glycine residue or about 2 to about 4 glycine residues. Therefore, after purification of the FN3 domain and cleavage of the His-tag from the polypeptide, one or more glycines may remain at the N-terminus or C-terminus. In some embodiments, when the His-tag is removed from the N-terminus, all glycine is removed. In some embodiments, if the His-tag is removed from the C-terminus, one or more of the glycines are retained.

In some embodiments, the FN3 domain that specifically binds to CD71 comprises the amino acid sequence of SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306, wherein the N-terminal methionine is It is maintained even after purification of the FN3 domain.

kit

In some embodiments, kits comprising an FN3 domain that binds CD71 are provided.

The kit can be used for therapeutic purposes and as a diagnostic kit.

In some embodiments, the kit includes an FN3 domain that binds to CD71 and a reagent for detecting the FN3 domain. In some embodiments, the kit includes bivalent FN3 domains. The kit includes instructions for use; Other reagents, such as labels, agents useful for chelating or otherwise coupling radioprotective compositions; A device or other material for preparing an FN3 domain that binds to CD71 for administration for imaging, diagnostic or therapeutic purposes; pharmaceutically acceptable carrier; and one or more other elements, including devices or other materials for administration to a subject.

In some embodiments, the kit comprises an FN3 domain that binds CD71 comprising the amino acid sequence of one of SEQ ID NOs: 1-7, 10, 12-219, 221-272, 292-299, or 304-306.

Uses of the CD71 binding FN3 domain

The FN3 domain or conjugate thereof that specifically binds to CD71 may assist in diagnosing, monitoring, regulating, treating, alleviating, preventing the development of a human disease or symptom of a particular pathology in a cell, tissue, organ, fluid or host in general; or It can be used to reduce its symptoms.

In some embodiments, the FN3 domain may facilitate delivery to CD71 positive tissue (e.g., skeletal muscle, smooth muscle) for treatment of muscle diseases.

In some embodiments, the FN3 domain may facilitate delivery to activated lymphocytes, dendritic cells, T-cells, NK cells, and B-cells or other immune cells for treatment of immunological diseases.

In some embodiments, the FN3 domain or conjugate thereof that specifically binds to CD71 can also be used to image CD71 positive tumor tissue in a subject. The methods disclosed herein can be used on animal patients belonging to any category. Examples of such animals include mammals such as humans, rodents, dogs, cats, and farm animals.

In some embodiments, a method of diagnosing a subject who has or is likely to develop cancer in a tissue based on the expression of CD71 by cells of the cancer tissue, a method of predicting success of immunotherapy, a method of predicting prognosis, and Treatment methods are provided.

In some embodiments, a method of detecting CD71-expressing cancer cells in tumor tissue is provided, the method comprising: obtaining a sample of tumor tissue from a subject; CD71 by contacting a small sample of tumor tissue with an FN3 domain that binds to CD71 comprising the amino acid sequence of any of SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306. Detecting whether it is expressed in tumor tissue and detecting binding between CD71 and FN3 domains. In some embodiments, methods of treating cancer in a subject in need thereof are provided. In some embodiments, the method includes administering to the subject a polypeptide or pharmaceutical composition that binds CD71. In some embodiments, the polypeptide of interest is an FN3 domain that binds CD71. In some embodiments, the polypeptide is a sequence such as SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306, or a polypeptide as provided herein linked or conjugated to a therapeutic agent. Contains peptides.

In some embodiments, CD71 cells are cells associated with inflammatory/immune diseases, such as CNS diseases, MS, and infectious diseases of the brain. In some embodiments, the polypeptide that binds CD71 is directed to the central nervous system. In some embodiments, methods of treating a neurological condition and/or brain tumor in a subject in need thereof are provided. In some embodiments, the method includes administering to the subject a polypeptide or pharmaceutical composition that binds CD71. In some embodiments, the polypeptide of interest is an FN3 domain that binds CD71. In some embodiments, the polypeptide is a sequence such as SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306, or a polypeptide as provided herein linked or conjugated to a therapeutic agent. Contains peptides. In some embodiments, the brain tumor is selected from the group consisting of non-malignant, benign, and malignant brain tumors. In some embodiments, the neurological condition Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Lafora's disease, Pompe's disease, adult polyglucocorticoid disease, stroke, spinal cord injury, ataxia, Bell's palsy, cerebral aneurysm, epilepsy, seizures. , Guillain-Barre syndrome, multiple sclerosis, muscular dystrophy, neurocutaneous syndrome, migraine, encephalitis, sepsis and myasthenia gravis.

In some embodiments, the polypeptide that binds CD71 is directed to muscle cells. In some embodiments, the method includes administering to the subject a polypeptide or pharmaceutical composition that binds CD71. In some embodiments, the polypeptide of interest is an FN3 domain that binds CD71. In some embodiments, the polypeptide is a sequence such as SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306, or a polypeptide as provided herein linked or conjugated to a therapeutic agent. Contains peptides.

In some embodiments, a method of treating Pompe disease (GSD2, acid alpha-glycosidase (GAA) deficiency) in a subject in need thereof is provided. In some embodiments, the method includes administering to the subject a polypeptide or pharmaceutical composition that binds CD71. In some embodiments, the polypeptide of interest is an FN3 domain that binds CD71. In some embodiments, the polypeptide is a sequence such as SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306, or a polypeptide as provided herein linked or conjugated to a therapeutic agent. Contains peptides.

In some embodiments, a method of treating a glycogen storage disease in a subject in need thereof is provided comprising administering a composition provided herein. In some embodiments, the glycogen storage disease is Cory's disease or Forbes' disease (GSD3, glycogen debranching enzyme (AGL) deficiency), McArdle disease (GSD5, muscle glycogen phosphorylase (PYGM) deficiency), type II diabetes/ Diabetic nephropathy, aldolase A deficiency GSD12, Lafora disease, hypoxia, Andersen's disease (GSD4, glycogen debranching enzyme (GBE1) deficiency), Tarui disease (GSD7, muscle phosphofructokinase (PFKM) deficiency) and adult poly. It is selected from the group consisting of gluconate body diseases. In some embodiments, the glycogen storage disease is glycogen synthase (GYS2) deficiency (GSD0), glucose-6-phosphatase (G6PC/SLC37A4) deficiency (GSD1, Von Gierke disease), Huss disease (GSD6, liver glycogen phosphorylation) Relays (PYGL) or muscle phosphoglycerate mutase (PGAM2) deficiency), phosphorylase kinase (PHKA2/PHKB/PHKG2/PHKA1) deficiency (GSD9), phosphoglycerate mutase (PGAM2) Deficiency (GSD10), muscle lactate dehydrogenase (LDHA) deficiency (GSD11), Fanconi-Bickel syndrome (GSD 11, glucose transporter (GLUT2) deficiency, aldolase A deficiency (GSD 12), β-enolase (ENO3) deficiency (GSD13) and glycogenin-1 (GYG1) deficiency (GSD15).

In some embodiments, the polypeptide that binds CD71 is directed against immune cells. In some embodiments, the polypeptide that binds CD71 is directed against dendritic cells, T-cells, NK cells, or B-cells. In some embodiments, methods of treating an autoimmune disease in a subject in need thereof are provided. In some embodiments, the method includes administering to the subject a polypeptide or pharmaceutical composition that binds CD71. In some embodiments, the polypeptide of interest is an FN3 domain that binds CD71. In some embodiments, the polypeptide is a sequence such as SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306, or a polypeptide as provided herein linked or conjugated to a therapeutic agent. Contains peptides. In some embodiments, the autoimmune disease is from the group consisting of rheumatoid arthritis, Hashimoto's autoimmune thyroiditis, celiac disease, type 1 diabetes, vitiligo, rheumatic fever, pernicious anemia/atrophic gastritis, alopecia areata, and immune thrombocytopenic purpura. is selected.

In some embodiments, the tissue can be tissue from any organ or anatomical system that expresses CD71.

In some embodiments, CD71 expression can be assessed using known methods such as immunohistochemistry or ELISA.

In some embodiments, methods of isolating CD71 expressing cells are provided, the methods comprising obtaining a sample from a subject; contacting the sample with an FN3 domain that binds to CD71 comprising an amino acid sequence of any of SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306, and a cell bound to the FN3 domain. It includes the step of isolating.

In some embodiments, a method is provided for detecting CD71-expressing cancer cells in tumor tissue, the method comprising detecting an amino acid of any of SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306. Forming a conjugate by conjugating the FN3 domain that binds to CD71 containing the sequence to a detectable label; administering the conjugate to the subject; and visualizing CD71-expressing cancer cells to which the zygote is bound.

In some embodiments, methods of treating cancer in a subject in need thereof are provided. In some embodiments, the method includes administering to the subject a polypeptide or pharmaceutical composition that binds CD71. In some embodiments, the polypeptide of interest is an FN3 domain that binds CD71. In some embodiments, the polypeptide is a sequence such as SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306, or a polypeptide as provided herein linked or conjugated to a therapeutic agent. Contains peptides. In some embodiments, a method of treating a subject with cancer is provided, comprising administering to the subject an FN3 domain that binds CD71. In some embodiments, the FN3 domain is conjugated to a therapeutic agent (e.g., a cytotoxic agent, an oligonucleotide such as siRNA, antisense, etc., an FN3 domain that binds another target, etc.).

In some embodiments, the subject has a solid tumor.

In some embodiments, the solid tumor is melanoma.

In some embodiments, the solid tumor is lung cancer. In some embodiments, the solid tumor is non-small cell lung cancer (NSCLC). In some embodiments, the solid tumor is squamous non-small cell lung cancer (NSCLC). In some embodiments, the solid tumor is non-squamous NSCLC. In some embodiments, the solid tumor is lung adenocarcinoma.

In some embodiments, the solid tumor is renal cell carcinoma (RCC).

In some embodiments, the solid tumor is mesothelioma.

In some embodiments, the solid tumor is nasopharyngeal carcinoma (NPC).

In some embodiments, the solid tumor is colorectal cancer.

In some embodiments, the solid tumor is prostate cancer. In some embodiments, the solid tumor is castration-resistant prostate cancer.

In some embodiments, the solid tumor is stomach cancer.

In some embodiments, the solid tumor is ovarian cancer.

In some embodiments, the solid tumor is gastric cancer.

In some embodiments, the solid tumor is liver cancer.

In some embodiments, the solid tumor is pancreatic cancer.

In some embodiments, the solid tumor is thyroid cancer.

In some embodiments, the solid tumor is squamous cell carcinoma of the head and neck.

In some embodiments, the solid tumor is carcinoma of the esophagus or gastrointestinal tract.

In some embodiments, the solid tumor is breast cancer.

In some embodiments, the solid tumor is fallopian tube cancer.

In some embodiments, the solid tumor is brain cancer.

In some embodiments, the solid tumor is urethral cancer.

In some embodiments, the solid tumor is genitourinary cancer.

In some embodiments, the solid tumor is endometriosis.

In some embodiments, the solid tumor is cervical cancer.

In some embodiments, the solid tumor is a metastatic lesion of cancer.

In some embodiments, the subject has a hematological malignancy. In some embodiments, the hematologic malignancy is lymphoma, myeloma, or leukemia. In some embodiments, the hematologic malignancy is B cell lymphoma. In some embodiments, the hematological malignancy is Burkitt's lymphoma. In some embodiments, the hematological malignancy is Hodgkin's lymphoma. In some embodiments, the hematologic malignancy is non-Hodgkin lymphoma.

In some embodiments, the hematological malignancy is myelodysplastic syndrome.

In some embodiments, the hematological malignancy is acute myeloid leukemia (AML). In some embodiments, the hematological malignancy is chronic myeloid leukemia (CML). In some embodiments, the hematologic malignancy is chronic myelomonocytic leukemia (CMML).

In some embodiments, the hematological malignancy is multiple myeloma (MM).

In some embodiments, the hematological malignancy is a plasmacytoma.

In some embodiments, the compositions or pharmaceutical compositions provided herein can be administered alone or in combination with other therapeutic agents, i.e., simultaneously or sequentially. In some embodiments, the other or additional therapeutic agent is another anti-tumor agent or therapeutic agent. Various tumor types and tumor stages require the use of various adjuvant compounds useful in the treatment of cancer. For example, the compositions provided herein can be used in combination with various chemotherapeutic agents, such as taxol, tyrosine kinase inhibitors, leucovorin, fluorouracil, irinotecan, phosphatase inhibitors, MEK inhibitors, among others. The composition may also be used in combination with drugs that modulate the immune response against tumors, especially anti-PD-1 or anti-CTLA-4. Additional therapeutic agents may be agents that modulate the immune system, such as antibodies targeting PD-1 or PD-L1.

In some embodiments, the polypeptide that binds CD71 is directed to the central nervous system. In some embodiments, methods of treating a neurological condition and/or brain tumor in a subject in need thereof are provided. In some embodiments, the method includes administering to the subject a polypeptide or pharmaceutical composition that binds CD71. In some embodiments, the polypeptide of interest is an FN3 domain that binds CD71. In some embodiments, the polypeptide is a sequence such as SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306, or a polypeptide as provided herein linked or conjugated to a therapeutic agent. Contains peptides. In some embodiments, the brain tumor is selected from the group consisting of non-malignant, benign, and malignant brain tumors. In some embodiments, the neurological condition is Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Lafora disease, Pompe disease, adult polyglucosanoma disease, stroke, spinal cord injury, ataxia, Bell's palsy, cerebral aneurysm, epilepsy, It is selected from the group consisting of seizures, Guillain-Barre syndrome, multiple sclerosis, muscular dystrophy, neurocutaneous syndrome, migraine, encephalitis, sepsis and myasthenia gravis. In some embodiments, a method of treating a neurological condition and/or brain tumor in a subject, the method comprising administering to the subject an FN3 domain that binds CD71, wherein the FN3 domain is a therapeutic agent (e.g., cytotoxic first, oligonucleotides such as siRNA, antisense, etc., FN3 domains that bind to another target, etc.).

In some embodiments, a method of treating Pompe disease (GSD2, acid alpha-glycosidase (GAA) deficiency) in a subject in need thereof is provided. In some embodiments, the method includes administering to the subject a polypeptide or pharmaceutical composition that binds CD71. In some embodiments, the polypeptide of interest is an FN3 domain that binds CD71. In some embodiments, the polypeptide is a sequence such as SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306, or a polypeptide as provided herein linked or conjugated to a therapeutic agent. Contains peptides. In some embodiments, a method of treating Pompe disease (GSD2, acid alpha-glycosidase (GAA) deficiency) in a subject comprises administering to the subject an FN3 domain that binds CD71, wherein the FN3 domain is a therapeutic agent (e.g. For example, cytotoxic agents, oligonucleotides such as siRNA, antisense, etc., FN3 domains that bind to another target, etc.).

In some embodiments, the polypeptide that binds CD71 is directed against immune cells. In some embodiments, the polypeptide that binds CD71 is directed against dendritic cells. In some embodiments, methods of treating an autoimmune disease in a subject in need thereof are provided. In some embodiments, the method includes administering to the subject a polypeptide or pharmaceutical composition that binds CD71. In some embodiments, the polypeptide of interest is an FN3 domain that binds CD71. In some embodiments, the polypeptide is a sequence such as SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306, or a polypeptide as provided herein linked or conjugated to a therapeutic agent. Contains peptides. In some embodiments, the autoimmune disease is from the group consisting of rheumatoid arthritis, Hashimoto's autoimmune thyroiditis, celiac disease, type 1 diabetes, vitiligo, rheumatic fever, pernicious anemia/atrophic gastritis, alopecia areata, and immune thrombocytopenic purpura. is selected. In some embodiments, a method of treating an autoimmune disease in a subject comprises administering to the subject an FN3 domain that binds CD71, wherein the FN3 domain is a therapeutic agent (e.g., a cytotoxic agent, an oligonucleotide, e.g., siRNA). , antisense, etc., an FN3 domain that binds to another target, etc.).

In some embodiments, the FN3 domain or conjugate thereof that specifically binds to CD71 is used to diagnose, monitor, control, treat, alleviate, or cause the development of a human disease or symptom of a particular pathology in a cell, tissue, organ, body fluid, or host in general. It can be used to aid or reduce prevention, and also exhibits properties that allow it to cross the blood brain barrier. The blood-brain barrier (BBB) prevents most macromolecules (e.g., DNA, RNA, and polypeptides) and many small molecules from entering the brain. The BBB is mainly composed of specialized endothelial cells with very limited tight junctions and, consequently, the passage of large and small substances from the blood to the central nervous system is controlled by the BBB. This structure makes the treatment and management of patients with neurological diseases and disorders (e.g., brain cancer) difficult because many therapeutic agents cannot be delivered with desirable efficiency across the BBB. Additional conditions associated with disruption of the BBB include stroke, diabetes, seizures, hypertensive encephalopathy, acquired immunodeficiency syndrome, traumatic brain injury, multiple sclerosis, Parkinson's disease (PD), and Alzheimer's disease. This ability includes, for example: astrocytoma, medulloblastoma, glioma, ependymoma, blastoma (pineadenoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma and congenital tumors; or spinal cancer, such as brain cancer, including neurofibroma, meningioma, glioma, and sarcoma. In certain embodiments, the FN3 domain that specifically binds to CD71 comprises an amino acid sequence of one of SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306, or a conjugate thereof: , for example, is useful for delivering therapeutic or cytotoxic agents across the blood brain barrier.

In some embodiments, the polypeptide capable of facilitating transport of a therapeutic agent across the BBB is a protein comprising the sequence of SEQ ID NOs: 1-7, 10, 12-219, 221-272, 292-299, or 304-306. .

“Treat” or “treatment” refers to therapeutic treatment and preventive measures, with the goal of preventing or slowing down (alleviating) undesirable physiological changes or disorders, such as the development or spread of cancer. In some embodiments, the beneficial or desired clinical outcome is alleviation of symptoms, reduction of disease severity, stabilization (i.e., not worsening) of disease, delay of disease progression, whether detectable or non-detectable. or slowing down, improvement or alleviation of disease state and remission (whether partial or total). “Treatment” can also mean prolonging survival compared to expected survival without treatment. People in need of treatment include not only those who already have the condition or disorder, but also those who are prone to the condition or disorder or those in need of preventing the condition or disorder.

“Therapeutically effective amount” refers to an amount that is effective at the dosage and duration necessary to achieve the desired therapeutic result. The therapeutically effective amount of the FN3 domain that specifically binds to CD71 may vary depending on factors such as the individual's disease state, age, gender, and weight. Exemplary indicators of an FN3 domain specifically binding to effective CD71 are improved patient well-being, reduction or shrinkage of tumor size, arrest or slowing of tumor growth, and/or absence of cancer cell metastasis to other locations in the body.

Administration/Pharmaceutical Composition

In some embodiments, pharmaceutical compositions are provided of an FN3 domain that specifically binds to CD71, optionally conjugated to a detectable label, therapeutic agent, or cytotoxic agent disclosed herein, and a pharmaceutically acceptable carrier. For therapeutic use, the FN3 domain that specifically binds to CD71 can be prepared into a pharmaceutical composition comprising an effective amount of the domain or molecule as an active ingredient in a pharmaceutically acceptable carrier. “Carrier” refers to a diluent, adjuvant, excipient, or vehicle with which an active compound is administered. These vehicles can be liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin such as peanut oil, soybean oil, mineral oil, sesame oil, etc. For example, 0.4% saline and 0.3% glycine can be used. These solutions are sterile and are generally free of particulate matter. They can be sterilized by existing, well-known sterilization techniques (e.g., filtration). The composition may contain pharmaceutically acceptable auxiliary substances necessary to approximate physiological conditions, such as pH adjusters and buffers, stabilizers, thickeners, lubricants and colorants. The concentration of the molecules disclosed herein in such pharmaceutical formulations can vary widely, i.e., from less than about 0.5% by weight, typically at least about 1% by weight to up to 15% or 20% by weight, depending on the particular mode of administration chosen. It will be selected based on required capacity, liquid volume, viscosity, etc. Suitable vehicles and formulations comprising other human proteins, such as human serum albumin, are described, for example, in Remington: The Science and Practice of Pharmacy, ^21st Edition, Troy, DB ed., Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing pp 691-1092, especially pp. [Ref. 958-989].

Modes of administration for therapeutic use of the FN3 domains disclosed herein include parenteral administration, e.g., intradermal, intramuscular, intraperitoneal, intravenous or subcutaneous, pulmonary; Dosage forms in the form of transmucosal (oral, intranasal, vaginal, rectal), tablets, capsules, solutions, powders, gels, particles; Syringes, implantable devices, osmotic pumps, cartridges, micropumps; or any suitable route for delivering the agent to the host, such as using the formulation contained in any other means recognized by those skilled in the art, as is well known in the art. Site-specific administration includes, for example, intra-articular, intra-bronchial, intra-abdominal, intra-capsular, intra-cartilaginous, intracavitary, intra-abdominal, intra-cerebellar, intraventricular, intracolon, intracervical, intragastric, intrahepatic, intracardiac, intraosseous, pelvic. Intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravascular, intravesical, intralesional, vagina, rectal, This can be achieved by buccal, sublingual, intranasal, or transdermal delivery.

The pharmaceutical composition may be supplied as a kit containing a container containing the pharmaceutical composition as described herein. Pharmaceutical compositions may be presented, for example, in the form of injectable solutions for single or multiple doses or as sterile powders to be reconstituted prior to injection. Alternatively, such kits may include a dry powder disperser, liquid aerosol generator, or nebulizer for administration of the pharmaceutical composition. Such kits may additionally contain written information regarding the indications and directions for use of the pharmaceutical composition.

Example

The following examples illustrate embodiments disclosed herein. These examples are provided for illustrative purposes only, and the embodiments should in no way be construed as limited to these examples, but rather should be construed to include any and all modifications evidenced as a result of the teachings provided herein. Those skilled in the art will readily recognize various non-critical parameters that can be changed or modified to produce essentially similar results.

Example 1. Construction of Tencon library with randomized loops

Tencon (SEQ ID NO: 276) is derived from the consensus sequence of 15 FN3 domains from human tenascin-C (Jacobs et al., Protein Engineering, Design, and Selection, 25:107-117, 2012; US Pat. No. 8,278,419). The fibronectin type III (FN3) domain is an engineered immunoglobulin-like scaffold. Tencon's crystal structure shows six surface-exposed loops connecting seven beta-strands. These loops or selected residues within each loop can be randomized to build a library of fibronectin type III (FN3) domains that can be used to select new molecules that bind to specific targets.

Various libraries were created using the Tencon scaffold and various design strategies. In general, libraries TCL1 and TCL2 produced good binders. The creation of TCL1 and TCL2 libraries is described in detail in International Publication No. WO/2014081944A2.

Example 2: Generation of Tencon libraries with alternative binding surfaces

The choice of residues to randomize in a particular library design dictates the overall shape of the generated interaction surface. An (Koide et al., Proc. Natl. Acad. Sci. USA 104: 6632-6637, 2007). In contrast, the ankyrin repeat scaffold protein selected to bind MBP was found to have a much more planar interaction surface and bind to the outer surface of MBP away from the active protein (Binz et al., Nat. Biotechnol. 22: 575-582, 2004). These results suggest that the shape (curved vs. flat) of the binding surface of the scaffold molecule can dictate which target protein or specific epitopes on the target protein can be effectively bound by the scaffold. Published efforts on engineering protein scaffolds containing FN3 domains for protein binding have relied on engineering adjacent loops for target binding to generate curved binding surfaces. This approach may limit the number of targets and epitopes that these scaffolds can access.

Tencone and other FN3 domains contain two sets of CDR-like loops on opposite sides of the molecule, the first set being formed by BC, DE, and FG loops, and the second set being formed by AB, CD, and EF loops. do. The two sets of loops are separated by a beta-strand that forms the core of the FN3 structure. By rotating Tencon's image by 90 degrees, alternative surfaces can be visualized. This slightly concave surface is formed by the CD and FG loops and the two antiparallel beta-strands, C and F beta-strands, and is referred to herein as the C-CD-F-FG surface. The C-CD-F-FG surface can be used as a template to design libraries of protein scaffold interaction surfaces by randomizing the subset of residues that form the surface. The beta-strand has side chains and repeats of all other residues exposed on the surface of the protein. Accordingly, libraries can be created by randomizing some or all of the surface exposed residues of the beta strand. By selecting appropriate residues in the beta-strand, the self-specificity of the Tencon scaffold should be minimally compromised while providing a unique scaffold surface for interaction with other proteins.

A full description of the methods used to build these libraries is described in US Publication No. 2013/0226834.

The two beta strands that form the C-CD-F-FG surface in tencon27 have a total of 9 surface exposed residues that can be randomized; C-strand: S30, L32, Q34, Q36; The F-strand has: E66, T68, S70, Y72, and V74, while the CD loop has 6 potential residues: S38, E39, K40, V41, G42, and E43, and the FG loop has 7 potential residues: K75. , G76, G77, H78, R79, S80 and N81. Because the theoretical size of the library would be larger if all 22 residues were randomized, these residues were selected for inclusion in the TCL14 design.

Thirteen positions in Tencon were selected for randomization: L32, Q34 in the C-strand and Q36, S38, E39, K40 in the CD-loop and V41, T68, S70 and Y72 in the F-strand and H78 in the FG-loop. , R79 and N81. On the C and F strands, S30 and E66 were not randomized as they lie just beyond the CD and FG loops and do not appear to be clearly part of the C-CD-F-FG surface. For the CD loop, G42 and E43 are not randomized to glycine, providing flexibility and can be useful in the loop region, and E43 is at the intersection of the surface. The FG loop excluded K75, G76, G77, and S80. For the above reasons, glycine was excluded, and a closer examination of the crystal structure showed that S80 forms major contacts with the core, helping to form a stable FG loop. K75 does not face the surface of the C-CD-F-FG surface and was a less attractive candidate for randomization. Although the above-mentioned residues were not randomized in the original TCL14 design, they provide additional diversity for new selections or subsequent library designs, for example, for affinity matured libraries against selected TCL14 target-specific hits. may be included in

After the production of TCL14, three additional Tencon libraries of similar design were produced. These two libraries, TCL19, TCL21 and TCL23, were randomized at the same positions as TCL14 (see above), but the distribution of amino acids occurring at these positions was altered. TCL19 and TCL21 were designed so that the 18 natural amino acids were equally distributed at all positions (5.55% each) except for cysteine and methionine. TCL23 was designed so that each randomized position was similar to the amino acid distribution found in the HCDR3 loop of a functional antibody (Birtalan et al., J. Mol. Biol. 377: 1518-1528, 2008). As with the TCL21 library, cysteine and methionine were excluded.

A third additional library was constructed to expand the potential target binding surface of the other libraries. In this library TCL24, four additional Tencon positions were randomized compared to libraries TCL14, TCL19, TCL21 and TCL23. These positions include N46 and T48 from the D strand and S84 and I86 from the G strand. Positions 46, 48, 84, and 86 are such that the side chains of these residues are surface exposed from beta-strands D and G and are adjacent to randomized portions of the C and F strands, resulting in an accessible surface area for binding to the target protein. It was specifically chosen because it increases. The amino acid distribution used at each position for TCL24 is the same as described for TCL19 and TCL21.

Generation of TCL21, TCL23 and TCL24 libraries

To control amino acid distribution, a TCL21 library was generated using Colibra library technology (Isogenica). To control amino acid distribution, TCL19, TCL23, and TCL24 gene fragments were generated using Slonomics technology (Morphosys). Each after initial synthesis using PCR for selection using the CIS-Display system (Odegrip et al., Proc. Natl. Acad. Sci. USA 101: 2806-2810, 2004) as described above for loop libraries. The library was amplified and then ligated into the gene for RepA.

Example 3: Selection of fibronectin type III (FN3) domains that bind CD71

Panning and biochemical screening

The FN3 domain specific for human CD71 was selected via CIS-Display (Odegrip et al 2004) using a recombinant biotinylated CD71 extracellular domain with an N-terminal 6His tag (SEQ ID NO: 309) (Sino Biologics). For in vitro transcription and translation (ITT), 3 μg of DNA from FN3 domain libraries TCL18, TCL19, TCL21, TCL23 and TCL24 were used, and unbound library members were removed by washing. DNA from the target protein was eluted by heating and amplified by PCR using KOD polymerase for additional rounds of panning. During each round, the concentration of target CD71 was successively lowered from 400 nM to 100 nM and the washing stringency was increased to isolate high-affinity binders. The results from 5 rounds of panning were subjected to 4 additional rounds for off-rate selection. The biotinylated target antigen concentration decreased to 25 nM in rounds 6 and 7, and to 2.5 nM in rounds 8 and 9.

After panning, the genes encoding the selected FN3 domains were amplified by PCR, subcloned into pET vectors modified to contain ligase-independent cloning sites, and cloned into BL21 (DE3) for soluble expression in E. coli using standard molecular biology techniques. ) (Stratagene) cells were transformed. A gene sequence encoding a C-terminal poly-histidine tag was added to each FN3 domain to enable purification and detection.

To screen for FN3 domains that specifically bind to CD71, streptavidin-coated Maxisorp plates (Nunc catalog 436110) were blocked for 1 hour in Starting Block T20 (Pierce) and then incubated with biotinylated CD71 (from panning). (using the same antigen as) or a negative control (unrelated Fc-fused recombinant protein and human serum albumin) for 1 hour. The plate was rinsed with TBST and the diluted lysate was applied to the plate for 1 hour. After additional rinses, wells were treated with HRP-conjugated anti-V5 tag antibody (Abcam, ab1325) for 1 hour and then assayed by POD (Roche, 11582950001). DNA from FN3 domain lysates with ELISA signals at least 10-fold higher than the streptavidin control was sequenced, resulting in 23 unique and readable FN3 domain sequences isolated from 9 rounds of screening.

Size exclusion chromatography analysis

The aggregation state of the anti-CD71 FN3 domain was determined using size exclusion chromatography. An aliquot (10 μl) of each purified FN3 domain was injected onto a Superdex 75 5/150 column (GE Healthcare) at a flow rate of 0.3 ml/min in a mobile phase of PBS (pH 7.4). Elution from the column was monitored by absorbance at 280 nm. Tencon protein was included as a control in each run. Elution profiles were analyzed using Agilent ChemStation software.

High-speed mass expression and conjugation

Confirmed clones were grown in two replicates of 5 ml of culture in 24 well deep block plates. Briefly, 150 μl of the overnight culture was seeded in 5 ml/well of TB medium supplemented with 50 μg/ml kanamycin and grown for approximately 3 hours at 37°C with shaking at 220 rpm (OD600 to 1). Cultures were induced using IPTG for an additional 4 hours at 37°C and 220 rpm to a final concentration of 1mM. The bacterial pellet was recovered by centrifugation at 2250xg for 15 minutes. 600 μl/well of BugBuster HT (Novagen) supplemented with 0.2 mg/ml lysozyme (Sigma) was added to each well; The pellet was separated with a pipette and shaken vigorously on a platform shaker for approximately 30 minutes until the pellet dissolved. Plates were spun at 2250xg for 15 minutes to make the lysates clear, and two 600 μl aliquots were combined for each sample. The His-tagged FN3 domain was purified on His Trap plates (GE) according to the manufacturer's instructions and then buffer exchanged into TBS using Zeba Spin 7K desalting plates (Thermo Scientific). Protein concentration was evaluated using Nanodrop. For conjugation to GlyGly-VC-MMAF (SEQ ID NO: 310), the FN3 domain (30 μM) was mixed with 150 μM GlyGlyVC-MMAF (SEQ ID NO: 310) (Concortis) and 1 μM Sortase A in a total volume of 200 μl. Conjugate for 1.5 hours at room temperature and purify again using 96 well His Multitrap HP plates from GE Healthcare according to the manufacturer's instructions. The buffer was exchanged for PBS using a Zeba desalting plate, then sterile filtered using a Multiscreen HTS GV plate (Durapore) and centrifuged at 3000xg for 2 minutes. Concentration was evaluated with Nanodrop.

CD71-mediated SK-BR3 cell killing assay.

Cell killing was assessed by measuring the viability of the CD71-overexpressing human tumor cell line H1573 w/SKBR3 after exposure to cysteine variant-cytotoxin conjugates. Cells were seeded at 7000/well in 100 μl/well phenol red-free RPMI medium (Gibco11835-030) containing 5% fetal calf serum (Gibco) in black well clear bottom tissue culture-treated plates (Falcon 353219). ting. Cells were allowed to attach overnight at 37°C in a humidified 5% CO2 atmosphere. Media was aspirated from 96-well plates and cells were treated with 50 μl fresh medium and 2× inhibitor consisting of 50 μl fresh medium. Cell viability was determined at 70 hours by an endpoint assay using Cell TiterGlo (Promega). IC50 values were determined by fitting the data to an equation for a sigmoidal dose response with variable slope using GraphPad Prism 5 (GraphPad Software).

Binding of selected clones by dose-response ELISA

Selected clones were analyzed by ELISA to determine EC50 values for binding. Briefly, Maxisorb plates were coated with 5 mg/ml streptavidin overnight at 4°C. The plate was then blocked with StartingBlock (ThermoFisher) for 1 hour at room temperature and then washed with TBS-Tween. Biotinylated CD71 (2 mg/ml) was captured in streptavidin plates, and serially diluted FN3 protein was added to the appropriate wells for 1 hour at room temperature. After washing, bound FN3 protein was detected using anti-V5 tag antibody conjugated to HRP and POD substrates and a luminescent plate reader. EC50 values for binding were determined by plotting luminescence values as a function of concentration and fitting to a dose response using PRISM.

Confirmation of FN3 domain internalization via toxin conjugate. The FN3 domain was conjugated to the cytotoxic tubulin inhibitor monomethyl auristatin F (MMAF) via an enzyme-cleavable Val-Cit linker or a non-cleavable PEG4 linker (VC-MMAF) using the methodology described for NEM conjugation. . Cell killing was assessed by measuring the viability of SKBR-3 cells after exposure to cysteine variant-cytotoxin conjugates. Plating cells at 3000/well in 50 μl/well of phenol red RPMI medium (Gibco, 11875093) containing 10% fetal bovine serum (Gibco) in white well opaque bottom tissue culture-treated plates (Fisher, PI15042). did. Cells were allowed to attach overnight at 37°C in a humidified 5% CO2 atmosphere. Cells were treated with 25 μl of fresh medium and 25 μl of 4Х inhibitor consisting of fresh medium. Cell viability was determined at 72 hours by an endpoint assay using Cell TiterGlo (Promega). IC50 values were determined by fitting the data to an equation for a sigmoidal dose response with variable slope using GraphPad Prism (GraphPad Software).

Bivalent FN3 protein

Bivalent FN3 proteins were produced using two FN3 domains linked by a four repeat G/S linker or other appropriate polypeptide linker. Bivalent FN3 protein was conjugated to VC-MMAF as described and assessed for cytotoxicity in SK-BR3 cells. IC50 values for bivalent molecules are often found to be better than monovalent versions.

Competition for transferrin binding and internalization

FN3 domain vcMMAF conjugates were screened for competition with human transferrin using the cytotoxicity assay described above. The FN3 domain was screened in the absence or presence of 0.6 μM holo-human transferrin (T0665-100MG).

pHrodo-Tf assay

CD71-targeted centirin was evaluated for its ability to compete with transferrin for binding to the transferrin receptor. Cells were treated with transferrin directly conjugated to pHrodo-Red, a dye that fluoresces in acidic compartments and thus becomes visible upon cellular uptake into endosomal and lysosomal compartments.

Imaging of pHrodo-transferrin (pHrodo-Tf) was performed in incucyte to measure Tf uptake in real time. Incubation of cells with pHrodo-Tf and molecules that compete with Tf for CD71 binding reduces or eliminates pHrodo signaling. Centirin, which does not compete with Tf for CD71 binding, does not affect pHrodo signaling.

Example 4: Selection of fibronectin type III (FN3) domains that bind CD71 and do not compete with transferrin

To identify CD71-binding FN3 domains that do not or minimally compete with transferrin, an unbiased CIS-display strategy was designed. Briefly, using the yield recovered after five rounds of panning against the ECD of human CD71 (Example 3), 1) a wash with human holo transferrin to elute the FN3 domain bound to the same site as transferrin before the final elution step. An additional round of off-rate selection was performed as described in Example 3, adding step or 2) elution of the FN3 domain conjugate with the monoclonal antibody OKT9. The FN3 domain recovered from the transferrin wash strategy and OKT9 elution strategy was PCR amplified and cloned into pET vector as previously described (Example 3). The 228 FN3 domains that specifically bound to huCD71 were confirmed by solution ELISA for binding to the huCD71 ECD. A subset of unique complexes were analyzed by SEC, conjugated to MMAF, and then assessed for internalization via cell viability assay in SKBR-3 cells +/- holo human transferrin. The polypeptide was found to be internalized by the receptor. Integral Molecular used a membrane proteome array to profile the specificity of ABX1198 (SEQ ID NO: 209), ABX1142 (SEQ ID NO: 209 + His-tag), and ABX1100 (SEQ ID NO: 209 + siRNA pair with linker) against a library of human membrane proteins. (MPA) assay was performed. The MPA library contains more than 6000 human membrane proteins, including 94% of all single-pass, multi-pass and GPI-anchored proteins, including GPCRs, ion channels and transporters, each of which is unique in the avian QT6 cell background. It is expressed clearly. Flow cytometry is used to directly detect ligands (FN3 domains) that bind to individually expressed membrane proteins in unfixed cells.

ABX1198 (SEQ ID NO: 209), ABX1142 (SEQ ID NO: 209 + His-tag) and ABX1100 (SEQ ID NO: 209 + siRNA pair with linker) at 1.25 μg/ml, 1.25 μg/ml and 0.31 μg/ml for MPA. Screening was conducted at the concentration with the optimal signal/background noise ratio. Membrane protein targets identified in the screening were pursued in a validation procedure using serial dilutions of ligand and cells individually transfected with the identified targets.

Example 5. Knockdown of mRNA in muscle cells using CD71 FN3 domain-oligonucleotide conjugate.

The muCD71-binding FN3 domain was conjugated to siRNA oligonucleotides or antisense oligonucleotides (ASO) using maleimide chemistry through uniquely engineered cysteines in the FN3 domain. Cysteine substitutions may be as provided herein or may also be as provided in US Publication No. 20150104808, which is incorporated herein by reference in its entirety. siRNA or ASO were modified with standard chemical modifications and confirmed to be capable of knockdown of targeted mRNA in vitro. The FN3 domain-oligonucleotide conjugate was administered intravenously to mice at doses up to 10 mg/kg oligonucleotide payload. Mice were sacrificed at various time points after administration; Skeletal muscle, cardiac muscle and various other tissues will be recovered and stored in RNAlater™ (Sigma Aldrich) until needed. Target gene knockdown was assessed using the standard qPCR ΔΔC _T method and primers specific for target and control genes. Target genes have been shown to be knocked down in muscle, and this knockdown is enhanced by conjugating siRNA or ASO to the CD71 FN3 binding domain.

Example 6. Affinity maturation panning:

Four sequences (A, B, C, and D) that showed selective CD71 apical domain binding were the basis of the affinity maturation library. In each sequence, four amino acids (double underlined) that are part of the expanded sheet library are replaced with 18 amino acids (not including proline, methionine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, iso). Leucine, leucine, lysine, phenylalanine, serine, threonine, tryptophan, tyrosine, or valine). The new library was prepared by a) transferrin washing; b) OKT9 elution; c) advanced domain selection; d) The leading-edge domain, CD71_ECD, underwent selection for 4 rounds of selection. See the sequences of SEQ ID NOs: 288 to 291 below.

Example 7: FN3-siRNA conjugation and purification

ABX1005 was prepared by conjugating cysteine-modified FN3 CD71-49 (SEQ ID NO: 272) to ABX0214 (Table 6) via cysteine-specific chemistry using maleimide-modified siRNA. For cysteine-maleimide conjugation, 50 μM to 200 μM of the cysteine-containing FN3 domain in PBS was reduced with 10 mM tris(2-carboxyethyl)phosphine (TCEP) at room temperature (30 min) to generate free thiol. To remove TCEP, FN3 protein was precipitated with saturated ammonium sulfate solution and then mixed with the maleimide-modified siRNA duplex previously dissolved in water at a FN3-protein:siRNA molar ratio of approximately 1.5:1. After 1 h incubation at RT or 37°C, the reaction was stopped with N -ethyl maleimide (1 mM final NEM concentration in the reaction mixture).

The FN3-siRNA conjugate was purified in two steps: removing unreacted siRNA linker using IMAC chromatography (HisTrap HP) and removing unreacted FN3 protein using anion exchange chromatography-Capto-DEAE. The FN3-protein-siRNA conjugate was characterized by PAGE, analytical size exclusion chromatography, and LC/MS. The concentration of the conjugate was calculated based on the absorbance of the conjugate solution at 260 using Nanodrop.

FN3-siRNA in vivo activity in mice

Male CD-1 mice were treated with 10 mpk siRNA of ABX1005 (CD71 FN3 domain conjugated to siRNA) or an equimolar dose of ABX1007 (FN3-only control) in one or three intravenous doses. Tissues were collected 2 weeks after the final dose and processed for AHA-1 knockdown analysis by quantitative reverse transcription-polymerase chain reaction (RT-PCR). 18S ribosomal RNA was used as an endogenous control gene for RT-PCR. The level of knockdown was compared to vehicle-treated mice. siRNA-mediated knockdown of AHA-1 was observed in all muscle groups analyzed in this study (gastrocnemius, quadriceps, cardiac) (Figure 1).

Male C57/BL6 mice were treated with a single intravenous dose of 10mpk, 3mpk, or 1mpk siRNA of ABX1005. Tissues were collected 2 weeks after single administration and processed for analysis of AHA-1 knockdown by quantitative reverse transcription-polymerase chain reaction (RT-PCR). 18S ribosomal RNA was used as an endogenous control gene for RT-PCR. The level of knockdown was compared to vehicle-treated mice. Dose-dependent knockdown of AHA-1 was observed in all muscle groups analyzed in this study (gastrocnemius, quadriceps, diaphragm, and heart) (Figure 2).

These examples demonstrate that siRNA molecules conjugated to FN3 domains, such as the FN3 domain that binds to CD71 provided herein, can be used to deliver siRNA molecules as well as other active moieties to specific tissues and modulate the expression of specific targets. It shows.

Example 8 : CD71 FN3 domain siRNA conjugate binding specificity.

Integral Molecular (www.integralmolecular.com) performed a proprietary membrane proteome array (MPA) assay to profile the specificity of CD71 FN3 domain and CD71 FN3 domain siRNA conjugates against a library of human membrane proteins (Figure 3). MPA contains more than 6000 human membrane proteins, representing 94% of all single-pass, multi-pass and GPI-anchored proteins, including GPCRs, ion channels and transporters, with each membrane protein uniquely expressed in the avian QT6 cell background. encompasses. Flow cytometry was used to directly detect FN3 domains binding to individually expressed membrane proteins in unfixed cells.

FN3 domain and FN3 domain-siRNA conjugates were screened at concentrations with optimal signal/background noise ratios of 1.25 μg/ml or 0.31 μg/ml, respectively, for MPA. Membrane protein targets identified in the screening were validated using serial dilutions of the ligand on cells natively expressing the identified targets.

Example 9: In vivo comparison of CD71 centirin conjugate and CD71 monoclonal antibody conjugate.

The objective in this study was to determine the duration of pharmacodynamic activity of the instrumental centirin-AHA1 conjugate compared to the monoclonal antibody R17 conjugated with AHA1 siRNA. C57BL6/J male mice were administered a single intravenous bolus of 17.9 mg of instrumental centirin-AHA1 siRNA conjugate containing 10 mg AHA1 siRNA or 120 mg monoclonal antibody R17 conjugated with AHA1 siRNA containing 10 mg AHA1 siRNA. Gastrocnemius muscle tissue not exceeding 0.5 cm in any direction was later collected at 2, 4, and 8 weeks post-administration (N=3/time point) to ensure good penetration of RNA and incubated at 4°C for 24 h. After storage, it was stored at -80°C. Total RNA was isolated from the gastrocnemius muscle using the Qiagen RNeasy Fiber Tissue Kit. Using real-time quantitative PCR, expression levels of the target AHA1 and the endogenous control, Pgk1, were measured. Data were analyzed using the ΔΔCt method normalized to control animals administered vehicle only. Gene expression levels of AHA1 and Pgk1 for each animal in the treatment group are provided relative to the average of the 3-vehicle control group. Tools The percent knockdown of AHA1 mRNA in the AHA1-siRNA conjugate treatment group and the monoclonal antibody R17 conjugated with the AHA1 siRNA treatment group was determined by subtracting 100 from the percentage of remaining AHA1 mRNA levels.

CD71 centirin conjugate induces sustained gene knockdown at a fraction of the mAb conjugate dose. C57/B6 mice were administered a single dose (10 mg/kg siRNA) of the test conjugate. The relative RNA expression of AHA1 was measured in the gastrocnemius muscle at 2 weeks, 4 weeks, and 8 weeks after administration. Figure 4 and Table 7 present data demonstrating equivalent activity for mRNA knockdown in muscle, but the CD71 centirin conjugate requires a much lower conjugate dose.

Example 10: Centirin-siRNA conjugates are active in cynomolgus monkey (Macaca fascicularis) skeletal muscle and heart

NeutrAvidin-coated 96-well plates (Pierce, 15116) were washed with PBS-Tween (0.05%) and blocked with blocking buffer (Starting Block T20, ThermoFisher 37539) for 30 minutes. Biotinylated antigen (human CD71-ECD [Acro Biosystems TFR-H8243] or Cyno CD71-ECD [Acro Biosystems TFR-C8249]) was immobilized on a blocked plate at a concentration of 20 nM and incubated for 1 hour at room temperature. . Centirin samples were diluted in blocking buffer, titrated from 1000 nM to 0.0169 nM, and incubated for 2 hours at room temperature. Plates were washed with PBS-Tween. Anti-sentirin antibody prepared at 1:2500 in blocking buffer was added to the plate and incubated for 1 hour. Plates were washed with PBS-Tween. Anti-rabbit HRP antibody was prepared at 1:2500 in blocking buffer, added to the plate and incubated for 1 hour. Plates were washed and read using ELISA substrates on SpectraMax Paradigm (Roche, 11582950001). Figure 5 and Table 8 present data demonstrating that CD71 centirin as well as CD71 centirin conjugate bind effectively to both human and cyno CD71 and do not interfere with siRNA conjugate CD71 centirin binding.

The purpose of this study was to determine the pharmacodynamic (PD) activity of centirin-AHA1 siRNA conjugate in the cynomolgus monkey model. Two male cynomolgus monkeys were administered 17.12 mpk centirin-AHA1 siRNA conjugate containing 10 mpk AHA1 siRNA (N=2) or vehicle (N=2) via IV bolus into the right saphenous vein once weekly for 3 weeks. processed for a while. Four weeks after the last dose, skeletal muscle tissue (left and right gastrocnemius, left and right quadriceps, diaphragm, left and right biceps, gastrocnemius), smooth muscle tissue (jejunum), left and right heart, and non-skeletal muscle tissue (skin, liver, and kidneys) ) was collected, and the RNA was stored later to ensure good penetration of the RNA, and stored at 4°C for 24 hours. Total RNA was isolated from these tissues using the Qiagen RNeasy Fibrous Tissue Kit. Expression levels of target AHA1 and endogenous controls (ARL1, ARFGAP2, HPRT1, GAPDH, and Gys1) were measured by real-time quantitative PCR. Data were analyzed using the ΔΔCt method normalized to control animals administered vehicle only. An average of 2 samples (1 biopsy from each side of tissue) or 1 sample (1 biopsy) were taken for analysis. The percentage knockdown of AHA1 mRNA in the centirin-AHA1 siRNA conjugate treatment group and vehicle group was determined by subtracting 100 from the percentage of remaining AHA1 mRNA level. In each tissue, the percentage of AHA1 knockdown is shown in order from most to least AHA1 knockdown.

Centirin-siRNA AHA1 conjugate effectively knocked down mRNA levels in vivo in cynomolgus monkey muscle and heart, see Figure 6. Monkeys were administered 10 mg/kg of siRNA three times per week. mRNA levels were assessed on day 28 after three doses.

common method

Standard methods in molecular biology include Sambrook, Fritsch and Maniatis (1982 & 1989 2nd Edition, 2001 ^3rd Edition) Molecular Cloning, A Laboratory Manual , Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Sambrook and Russell (2001) Molecular Cloning, 3rd ^ed ., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Wu (1993) Recombinant DNA , Vol. 217, Academic Press, San Diego, CA)]. Standard methods are described in Ausbel, et al . (2001) Current Protocols in Molecular Biology, Vols.1-4 , John Wiley and Sons, Inc. New York, NY, which describes cloning in bacterial cells and DNA mutagenesis (Vol. 1), cloning in mammalian cells and yeast (Vol. 2), glycoconjugates and protein expression (Vol. 3), and bioinformatics (Vol. 4)] It also appears in

Protein purification methods including immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization have been described (Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 1, John Wiley and Sons, Inc., New York). Chemical analysis, chemical modifications, post-translational modifications, fusion protein production, and glycosylation of proteins have been described (see, e.g., Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 2, John Wiley and Sons, Inc., New York; Ausubel, et al. (2001) Current Protocols in Molecular Biology, Vol. 3, John Wiley and Sons, Inc., NY, NY, pp. 16.0.5-16.22.17; Sigma -Aldrich, Co. (2001) Products for Life Science Research, St. Louis, MO; pp. 45-89; Amersham Pharmacia Biotech (2001) BioDirectory, Piscataway, N.J., pp. 384-391]. The production, purification and fragmentation of polyclonal and monoclonal antibodies have been described (Coligan, et al. (2001) Current Protocols in Immunology, Vol. 1, John Wiley and Sons, Inc., New York; Harlow and Lane (1999) Using Antibodies, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Harlow and Lane, supra). Standard techniques for characterizing ligand/receptor interactions can be used (see, e.g., Coligan, et al. (2001) Current Protocols in Immunology, Vol. 4, John Wiley, Inc., New York) .

All references cited herein are incorporated by reference to the same extent as if each individual publication, database item (e.g., Genbank sequence or GeneID entry), patent application, or patent was specifically and individually indicated to be incorporated by reference. This specification, incorporated by reference, with respect to any individual publication, database entry (e.g., Genbank sequence or GeneID entry), patent application, or patent, is pursuant to 37 C.F.R. §1.57(b)(1), each is intended by the applicant to be incorporated by reference, even if not immediately adjacent to the dedicated statement that the citation is incorporated by reference, 37 C.F.R. Clearly identified under §1.57(b)(2). The inclusion of a dedicated statement incorporated by reference in the specification does not in any way weaken the general statement incorporated by reference. Citing a reference in this specification does not constitute an admission that the reference is relevant prior art, nor does it imply any acknowledgment of the content or date of such publication or document.

The present embodiments are not limited in scope by the specific embodiments described herein. Indeed, various modifications of the embodiments in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

The foregoing specification is deemed sufficient to enable any person skilled in the art to practice the embodiments. Various modifications of the embodiments in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and are within the scope of the appended claims.

SEQUENCE LISTING <110> ARO BIOTHERAPEUTICS COMPANY <120> CD71 BINDING FIBRONECTIN TYPE III DOMAINS <130> WO2022221505 <140> PCT/US2022/024773 <141> 2022-04-14 <150> 63/324,431 <151> 2022-03-28 <150> 63/174,752 <151> 2021-04-14 <160> 311 <170> PatentIn version 3.5 <210> 1 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 1 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Pro Ile Thr Tyr Ile Glu Ala Val Val Leu Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Gly Ile Ser Gly Val Lys Gly Gly His Asn 65 70 75 80 Ser Met Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 2 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 2 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Gln Gly Val Ala Arg Ala Phe Asp Ser Phe 20 25 30 Met Ile Asn Tyr Ser Glu Leu Phe Trp Met Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Val Val Arg Ile Lys Gly Val Lys Gly Gly Lys Gly 65 70 75 80 Ser Trp Pro Leu His Ala His Phe Thr Thr 85 90 <210> 3 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 3 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Asn Ile Glu Tyr Ala Glu Thr Arg Trp Tyr Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Val Val Pro Ile Asp Gly Val Lys Gly Gly Ile Ala 65 70 75 80 Ser Lys Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 4 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 4 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Gln Gly Val Ala Arg Ala Phe Asp Ser Phe 20 25 30 Leu Ile Thr Tyr Arg Asp Gln Ile Phe Ala Gly Glu Val Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Trp Ile Gln Gly Val Lys Gly Gly Ser Pro 65 70 75 80 Ser Ala Pro Leu Ser Ala Glu Ser Thr Thr 85 90 <210> 5 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 5 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Gln Gly Val Ala Arg Ala Phe Asp Ser Phe 20 25 30 Leu Ile Thr Tyr Arg Glu Gln Ile Phe Ala Gly Glu Val Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Trp Val Tyr Ile Trp Gly Val Lys Gly Gly Lys Pro 65 70 75 80 Ser Phe Pro Leu Arg Ala Gly Phe Thr Thr 85 90 <210> 6 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 6 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Pro Ile Ile Tyr Met Glu Thr Phe Ser Arg Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Arg Val Pro Ile Gly Gly Val Lys Gly Gly Ser Ser 65 70 75 80 Ser Cys Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 7 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 7 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Asp Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Gln Gly Val Ala Arg Ala Phe Asp Ser Phe 20 25 30 Leu Ile Thr Tyr Arg Glu Gln Ile Phe Ala Gly Glu Val Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Trp Ile Gln Gly Val Lys Gly Gly Ser Pro 65 70 75 80 Ser Ala Pro Leu Ser Ala Glu Phe Thr Thr 85 90 <210> 8 <400> 8 000 <210> 9 <400> 9 000 <210> 10 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 10 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Lys Ile Ala Tyr Ile Glu Thr Ala Thr Arg Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Val Val Pro Ile Pro Gly Val Lys Gly Gly Asn Thr 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 11 <400> 11 000 <210> 12 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 12 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Pro Tyr Ala Glu Pro Ser Pro Thr Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly His Leu 65 70 75 80 Ser Asp Pro Leu Ser Ala Ile Ser Thr Thr 85 90 <210> 13 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 13 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Leu Ile Ala Tyr Pro Glu Asp Gly Phe Arg Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Pro Ile Leu Gly Val Lys Gly Gly Gly Gly 65 70 75 80 Ser Gly Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 14 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 14 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Pro Ile Tyr Tyr Val Glu Asn Val Val Trp Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Trp Glu Val Ile Ile Gly Val Lys Gly Gly Gln Cys 65 70 75 80 Ser Arg Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 15 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 15 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Gln Gly Val Ala Arg Ala Phe Asp Ser Phe 20 25 30 Leu Ile Thr Tyr Arg Glu Gln Ile Phe Ala Gly Glu Val Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Cys Pro Val Trp Ile Gln Gly Val Lys Gly Gly Ser Pro 65 70 75 80 Ser Ala Pro Leu Ser Ala Glu Phe Thr Thr 85 90 <210> 16 <211> 89 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 16 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Gly Ile Ala Tyr Arg Glu Phe Arg Pro Ser Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Val Glu Thr Gly 50 55 60 Tyr Arg Asn Glu Val Val Ile Cys Gly Val Lys Gly Gly Pro Trp Ser 65 70 75 80 Gly Pro Leu Ser Ala Ile Phe Thr Thr 85 <210> 17 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 17 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Pro Ile Leu Tyr Thr Glu Cys Val Tyr Arg Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr His Val Pro Ile Thr Gly Val Lys Gly Gly Gly Gly 65 70 75 80 Ser Trp Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 18 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 18 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Asn Ile Met Tyr His Glu Ile Ile Tyr Val Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Pro Ile Glu Gly Val Lys Gly Gly Gly Thr 65 70 75 80 Ser Gly Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 19 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 19 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Ala Ile Thr Tyr Thr Glu Ala Ala Leu Cys Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Pro Ile Asn Gly Val Lys Gly Gly Gly Thr 65 70 75 80 Ser Gly Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 20 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 20 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ala Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Ile Asp Ser Phe 20 25 30 Pro Ile Asp Tyr Ser Glu Tyr Trp Trp Gly Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Leu Ile Thr Gly Val Lys Gly Gly Tyr Arg 65 70 75 80 Ser Gly Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 21 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 21 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Ser Ile Arg Tyr Asn Glu Phe Ile Val Ala Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asp Val Pro Ile Ala Gly Val Lys Gly Gly Gly Ala 65 70 75 80 Ser Trp Pro Leu Ser Ala Ile Val Thr Thr 85 90 <210> 22 <211> 88 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 22 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Trp Tyr Leu Glu Leu Gln Phe Ala Gly Glu Ala Ile Val Leu Thr Val 35 40 45 Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr 50 55 60 Glu Tyr Asn Val Pro Ile Thr Gly Val Lys Gly Gly Ile Ile Ser Phe 65 70 75 80 Pro Leu Ser Ala Ile Phe Thr Thr 85 <210> 23 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 23 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Ala Ile Trp Tyr His Glu Trp Tyr Gly Asp Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Pro Lys Pro 50 55 60 Gly Thr Glu Tyr Arg Val Arg Ile Ser Gly Val Lys Gly Gly Phe Glu 65 70 75 80 Ser Gly Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 24 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 24 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Met Ile Arg Tyr Gln Glu Gly Thr Arg Trp Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ile Val Met Ile Ala Gly Val Lys Gly Gly Gln Ile 65 70 75 80 Ser Leu Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 25 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 25 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Pro Ile Trp Tyr Leu Glu Lys Ser Tyr Gln Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Val Val Pro Ile Ile Gly Val Lys Gly Gly Arg Asp 65 70 75 80 Ser Cys Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 26 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 26 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Gln Gly Val Ala Arg Ala Phe Asp Ser Phe 20 25 30 Leu Ile Thr Tyr Arg Glu Gln Ile Phe Ala Gly Glu Val Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Trp Ile Gln Gly Val Lys Gly Gly Ser Pro 65 70 75 80 Ser Ala Pro Leu Ser Ala Glu Phe Thr Thr 85 90 <210> 27 <211> 89 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 27 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Arg Ile Ser Tyr Ala Glu Thr Val Arg Gln Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Val Glu Thr Gly 50 55 60 Tyr Arg Asn Trp Val Met Ile Leu Gly Val Lys Gly Gly Pro Gly Ser 65 70 75 80 Leu Pro Leu Ser Ala Ile Phe Thr Thr 85 <210> 28 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 28 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Gln Gly Val Val Arg Ala Phe Asp Ser Phe 20 25 30 Leu Ile Thr Tyr Arg Glu Gln Ile Phe Ala Gly Glu Val Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Trp Ile Gln Gly Val Lys Gly Gly Ser Pro 65 70 75 80 Ser Ala Pro Leu Ser Ala Glu Phe Thr Thr 85 90 <210> 29 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 29 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Trp Ile Glu Tyr Trp Glu Ala Val Gly Phe Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Phe Val Gly Ile Tyr Gly Val Lys Gly Gly Tyr Leu 65 70 75 80 Ser Ala Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 30 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400>30 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Ile Ile His Tyr Val Glu Gln Gln Leu Ile Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Pro Ile Thr Gly Val Lys Gly Gly Ala Cys 65 70 75 80 Ser Trp Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 31 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 31 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Thr Ile Glu Tyr Ser Glu His Pro Ile Asp Gly Glu Ala Ile Pro Leu 35 40 45 Phe Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Tyr Val Arg Ile His Gly Val Lys Gly Gly Trp Phe 65 70 75 80 Ser His Pro Leu Trp Ala Phe Phe Thr Thr 85 90 <210> 32 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 32 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Gln Gly Val Ala Arg Ala Phe Asp Ser Phe 20 25 30 Leu Ile Thr Tyr Arg Glu Gln Ile Phe Ala Gly Glu Val Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Gly Val Thr Ile Ala Gly Val Lys Gly Gly Trp Arg 65 70 75 80 Ser Lys Pro Leu Asn Ala Glu Ser Thr Thr 85 90 <210> 33 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 33 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Gly Ile Ala Tyr Val Glu Ser Tyr Trp Tyr Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Pro Ile Tyr Gly Val Lys Gly Gly Asp Gly 65 70 75 80 Ser Gly Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 34 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 34 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Thr Tyr Val Glu Leu Asn Leu Ala Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Pro Ile Leu Gly Val Lys Gly Gly Ser Leu 65 70 75 80 Ser Gln Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 35 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 35 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Pro Ile Ser Tyr Ile Glu Ser Ile Ala Asp Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Trp Val Ala Ile Val Gly Val Lys Gly Gly Pro Phe 65 70 75 80 Ser Trp Ser Leu Ser Ala Ile Val Thr Thr 85 90 <210> 36 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 36 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Gln Gly Val Ala Arg Ala Phe Asp Ser Phe 20 25 30 Leu Ile Thr Tyr Arg Glu Gln Ile Phe Ala Gly Glu Val Ile Val Pro 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Pro Ile Ala Gly Val Lys Gly Gly Gly Pro 65 70 75 80 Ser Ala Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 37 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 37 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Thr Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Pro Ile Tyr Tyr Trp Glu Val Thr Ile Thr Gly Glu Ala Ile Tyr Leu 35 40 45 Ser Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Asp Ile Pro Gly Val Lys Gly Gly Ala Ala 65 70 75 80 Ser Pro Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 38 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 38 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Pro Ile Leu Tyr Leu Glu His Thr Val Arg Ser Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Asp Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Cys Val Pro Ile Asp Gly Val Lys Gly Gly Leu Arg 65 70 75 80 Ser Arg Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 39 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 39 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Pro Ile Pro Tyr Thr Glu Pro Pro Asp Pro Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Leu Val Thr Ile Leu Gly Val Lys Gly Gly Ser Met 65 70 75 80 Ser Val Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 40 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 40 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Thr Ile Asp Tyr Trp Glu Asn Arg Cys Pro Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Cys Val Trp Ile Ser Gly Val Lys Gly Gly Tyr Ser 65 70 75 80 Ser Trp Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 41 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 41 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Gln Gly Val Ala Arg Ala Phe Asp Ser Phe 20 25 30 Leu Ile Thr Tyr Arg Glu Gln Ile Phe Ala Gly Glu Val Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Trp Ile Gln Gly Val Lys Gly Gly His Leu 65 70 75 80 Ser Asp Pro Leu Ser Ala Ile Val Thr Thr 85 90 <210> 42 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 42 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Leu Ile Pro Tyr Ala Glu Thr Ser Pro Ser Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Asp Tyr 65 70 75 80 Ser Glu Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 43 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 43 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Met Ile Val Tyr Tyr Glu Tyr Thr Arg Phe Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Thr Val Pro Ile Asp Gly Val Lys Gly Gly Gly Arg 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 44 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 44 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Pro Tyr Ala Glu Pro Ser Pro Thr Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly His Leu 65 70 75 80 Ser Asp Pro Leu Ser Ala Ile Val Thr Thr 85 90 <210> 45 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 45 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Gln Gly Val Ala Arg Ala Phe Asp Ser Phe 20 25 30 Leu Ile Thr Tyr Arg Glu Gln Ile Phe Ala Gly Glu Val Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Trp Ile Gln Gly Val Lys Gly Gly Ser Pro 65 70 75 80 Ser Ala Pro Leu Ser Ala Glu Phe Thr Thr 85 90 <210> 46 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 46 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Ile Ile Pro Tyr Ala Glu Val Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Lys Leu 65 70 75 80 Ser Leu Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 47 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 47 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Gly Ile Val Tyr Leu Glu Met Met Val Thr Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asp Val Pro Ile Leu Gly Val Lys Gly Gly Thr Arg 65 70 75 80 Ser Val Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 48 <211> 94 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 48 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Leu Ile Tyr Tyr Glu Glu Gly Tyr Leu Glu Tyr Tyr Tyr Ser Gly Glu 35 40 45 Ala Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr 50 55 60 Gly Leu Lys Pro Gly Thr Glu Tyr Tyr Val Gly Ile Val Gly Val Lys 65 70 75 80 Gly Gly Gly Leu Ser Gly Pro Leu Ser Ala Ile Ser Thr Thr 85 90 <210> 49 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 49 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Pro Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Asp Trp 65 70 75 80 Ser Leu Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 50 <211> 91 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 50 Met Ser Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu 1 5 10 15 Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser 20 25 30 Phe Thr Ile His Tyr Arg Glu Phe Gln Leu Ser Gly Glu Ala Ile Val 35 40 45 Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys 50 55 60 Pro Gly Thr Glu Tyr Asp Val Pro Ile Glu Gly Val Lys Gly Gly Pro 65 70 75 80 Gly Ser Arg Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 51 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 51 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Gln Gly Val Ala Arg Ala Phe Asp Ser Phe 20 25 30 Leu Ile Thr Tyr Arg Glu Gln Ile Phe Ala Gly Glu Val Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Cys Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Trp Ile Gln Gly Val Lys Gly Gly Ser Pro 65 70 75 80 Ser Ala Pro Leu Ser Ala Glu Phe Thr Thr 85 90 <210> 52 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 52 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Glu Ile Asp Tyr Asp Glu Leu Ala Ile Tyr Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Gly Val Arg Ile Pro Gly Val Lys Gly Gly Met Pro 65 70 75 80 Ser Leu Pro Leu Ser Ala Ile Val Thr Thr 85 90 <210> 53 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 53 Met Leu Pro Ala Pro Glu Asn Leu Val Val Ser Glu Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Gln Gly Val Ala Arg Ala Phe Asp Ser Phe 20 25 30 Leu Ile Thr Tyr Arg Glu Gln Ile Phe Ala Gly Glu Val Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Trp Ile Gln Gly Val Lys Gly Gly Ser Pro 65 70 75 80 Ser Ala Pro Leu Ser Ala Glu Ser Thr Thr 85 90 <210> 54 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 54 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Ala Ile Ala Tyr Gly Glu His Ile Val Ile Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Met Val Pro Ile Ala Gly Val Lys Gly Gly Pro Ile 65 70 75 80 Ser Leu Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 55 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 55 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Pro Tyr Ala Glu Pro Ser Pro Thr Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly His Leu 65 70 75 80 Ser Asp Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 56 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 56 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Ser Ile Gly Tyr Val Glu Leu Val Leu Leu Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asp Val Leu Ile Pro Gly Val Lys Gly Gly Ser Leu 65 70 75 80 Ser Arg Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 57 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 57 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Ala Ile Pro Tyr Ala Glu Leu Ser Arg Asn Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Thr Val Leu Ile His Gly Val Lys Gly Gly Cys Leu 65 70 75 80 Ser Asp Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 58 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 58 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 His Ile Glu Tyr Leu Glu Leu Ser Arg His Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Trp Val Met Ile Phe Gly Val Lys Gly Gly Gly Pro 65 70 75 80 Ser Lys Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 59 <211> 88 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 59 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Val Tyr Asn Glu Val His Trp Ile Gly Glu Ala Ile Val Leu Thr Val 35 40 45 Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr 50 55 60 Glu Tyr Phe Val Gly Ile Tyr Gly Val Lys Gly Gly His Trp Ser Lys 65 70 75 80 Pro Leu Ser Ala Ile Phe Thr Thr 85 <210>60 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400>60 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Glu Ile Asp Tyr Asp Glu Leu Ala Ile Tyr Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Gly Val Arg Ile Pro Gly Val Lys Gly Gly Met Pro 65 70 75 80 Ser Leu Pro Leu Ser Ala Ile Val Thr Thr 85 90 <210> 61 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 61 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Gln Ile Val Tyr Ser Glu Leu Trp Ile Lys Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Gln Val Pro Ile Pro Gly Val Lys Gly Gly Arg Asn 65 70 75 80 Ser Phe Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 62 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400>62 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Lys Ile Arg Tyr Thr Glu Thr Arg Ser Ile Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Cys Val Pro Ile Gly Gly Val Lys Gly Gly Asp Ser 65 70 75 80 Ser Trp Pro Leu Ser Ala Ile Ser Thr Thr 85 90 <210> 63 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 63 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Cys Ile Ser Tyr Tyr Glu Arg Met Gly Arg Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Met Val Tyr Ile Phe Gly Val Lys Gly Gly Leu Asn 65 70 75 80 Ser Leu Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 64 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400>64 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Val Tyr Ala Glu Pro Ile Pro Asn Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Arg Asn 65 70 75 80 Ser Asp Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 65 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400>65 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Lys Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Pro Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 66 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 66 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Thr Ile Asp Tyr Asp Glu Pro Arg Ser Pro Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Arg Val Phe Ile Trp Gly Ile Lys Gly Gly Asp Thr 65 70 75 80 Ser Phe Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 67 <211> 88 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 67 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Thr Ile Leu Tyr Ala Glu Gln Ala Gln Phe Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Ile Thr Gly Val Lys Gly Gly Thr Arg Ser Gly 65 70 75 80 Pro Leu Ser Ala Ile Ser Thr Thr 85 <210> 68 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 68 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Ile Ile Pro Tyr Ala Glu Val Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly His Leu 65 70 75 80 Ser Asp Pro Leu Ser Ala Ile Ser Thr Thr 85 90 <210> 69 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 69 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 His Ile Ala Tyr Glu Glu Thr Ala Thr Ser Gly Glu Ala Ile Tyr Leu 35 40 45 Arg Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Gly Val Glu Ile Glu Gly Val Lys Gly Gly Ala Arg 65 70 75 80 Ser Arg Pro Leu Tyr Ala Asp Phe Thr Thr 85 90 <210>70 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400>70 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Gln Gly Val Ala Arg Ala Phe Asp Ser Phe 20 25 30 Leu Ile Thr Tyr Arg Glu Gln Ile Phe Ala Gly Glu Val Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Trp Ile Gln Gly Val Lys Gly Gly Asp Leu 65 70 75 80 Ser Asn Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 71 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 71 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Pro Ile Ser Tyr Leu Glu Leu Ser Leu Tyr Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Gly Ile Ala Gly Val Lys Gly Gly Val Val 65 70 75 80 Ser Arg Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 72 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 72 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Thr Ile Gly Tyr Arg Glu Trp Tyr Trp Tyr Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Pro Ile Ser Gly Val Lys Gly Gly Leu Asp 65 70 75 80 Ser Phe Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 73 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 73 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Gln Gly Val Ala Arg Ala Phe Asp Ser Phe 20 25 30 Leu Ile Thr Tyr Arg Glu Gln Ile Phe Ala Gly Glu Val Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Trp Ile Gln Gly Val Lys Gly Gly Ser Pro 65 70 75 80 Ser Ala Pro Leu Ser Ala Glu Ser Thr Thr 85 90 <210> 74 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 74 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Ser Ile Thr Tyr Leu Glu Trp Trp Asn Leu Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Met Val Thr Ile Pro Gly Val Lys Gly Gly Met Ser 65 70 75 80 Ser Tyr Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 75 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 75 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Thr Ile Ser Tyr Gly Glu Glu Ala Leu Ile Gly Glu Ala Ile Tyr Leu 35 40 45 Arg Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Tyr Val His Ile Glu Gly Val Lys Gly Gly Ser Trp 65 70 75 80 Ser Gln Pro Leu Ala Ala Ala Phe Thr Thr 85 90 <210> 76 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 76 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Thr Ile Glu Tyr Tyr Glu Asn Ile Gly Ile Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Pro Ile Val Gly Val Lys Gly Gly Pro Tyr 65 70 75 80 Ser His Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 77 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 77 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Pro Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 78 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 78 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Gly Ile Gly Tyr Tyr Glu His Lys Arg Phe Gly Glu Ala Ile Gln Leu 35 40 45 Ser Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Glu Val Asp Ile Glu Gly Val Lys Gly Gly Val Leu 65 70 75 80 Ser Trp Pro Leu Phe Ala Glu Phe Thr Thr 85 90 <210> 79 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 79 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Val Ile Glu Tyr Thr Glu Arg Phe Trp Ser Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Pro Ile Asp Gly Val Lys Gly Gly Gln Cys 65 70 75 80 Ser Thr Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210>80 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400>80 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Trp Ile Asp Tyr Glu Glu Glu Gly Val Ile Gly Glu Ala Ile Tyr Leu 35 40 45 His Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Val Val Lys Ile His Gly Val Lys Gly Gly His Pro 65 70 75 80 Ser His Pro Leu Val Ala Val Phe Thr Thr 85 90 <210> 81 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 81 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Gln Gly Val Ala Arg Ala Phe Asp Ser Phe 20 25 30 Leu Ile Thr Tyr Val Glu Leu Arg His Leu Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Trp Ile Gln Gly Val Lys Gly Gly Ser Pro 65 70 75 80 Ser Ala Pro Leu Ser Ala Glu Phe Thr Thr 85 90 <210> 82 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 82 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Leu Ile Pro Tyr Ala Glu Thr Ser Pro Ser Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Asp Tyr 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 83 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 83 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Pro Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Ser Thr Thr 85 90 <210> 84 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 84 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Gln Gly Val Ala Arg Ala Phe Asp Ser Phe 20 25 30 Ser Ile Leu Tyr Leu Glu Leu Thr Pro Lys Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Trp Ile Gln Gly Val Lys Gly Gly Ser Pro 65 70 75 80 Ser Ala Pro Leu Ser Ala Glu Phe Thr Thr 85 90 <210> 85 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 85 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Ile Ile Glu Tyr Phe Glu Pro Ile Pro Ile Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ala Val Asn Ile Tyr Gly Val Lys Gly Gly Tyr Leu 65 70 75 80 Ser His Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 86 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 86 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Gln Gly Val Ala Arg Ala Phe Asp Ser Phe 20 25 30 Leu Ile Thr Tyr Arg Glu Gln Ile Phe Ala Gly Glu Val Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Cys Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Trp Ile Gln Gly Val Lys Gly Gly Ser Pro 65 70 75 80 Ser Ala Pro Leu Ser Ala Glu Phe Thr Thr 85 90 <210> 87 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 87 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Ala Ile Glu Tyr Thr Glu Phe Leu Tyr Ser Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Gly Val Pro Ile Asn Gly Val Lys Gly Gly Phe Val 65 70 75 80 Ser Pro Pro Leu Ser Ala Ile Val Thr Thr 85 90 <210> 88 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 88 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Pro Ile Lys Tyr Arg Glu Val Leu Arg Cys Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Thr Val Pro Ile Thr Gly Val Lys Gly Gly Phe Gly 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 89 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 89 Met Leu Pro Ala Pro Glu Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Trp Ile Glu Tyr Tyr Glu Gly Val Ile Gln Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Phe Val Ala Ile Trp Gly Val Lys Gly Gly Lys Trp 65 70 75 80 Ser Val Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 90 <211> 86 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400>90 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Gln Gly Val Ala Arg Ala Phe Asp Ser Phe 20 25 30 Leu Ile Thr Tyr Arg Glu Gln Ile Phe Ala Gly Glu Val Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Trp Ile Gln Gly Val Lys Gly Gly Ser Pro 65 70 75 80 Ser Ala Glu Phe Thr Thr 85 <210> 91 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 91 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Gln Ile His Tyr Trp Glu Thr Gln Gly Phe Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Leu Ile Pro Gly Val Lys Gly Gly Pro Ser 65 70 75 80 Ser Leu Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 92 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 92 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Pro Tyr Ala Glu Pro Ser Pro Thr Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly His Leu 65 70 75 80 Ser Asp Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 93 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 93 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Ala Ile Glu Tyr Tyr Glu Pro Val Pro Ala Gly Glu Ala Ile Tyr Leu 35 40 45 Asp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asp Val Thr Ile Tyr Gly Val Lys Gly Gly Tyr Tyr 65 70 75 80 Ser His Pro Leu Phe Ala Ser Phe Thr Thr 85 90 <210> 94 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 94 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Gln Gly Val Ala Arg Ala Phe Asp Ser Phe 20 25 30 Leu Ile Thr Tyr Arg Glu Gln Ile Phe Ala Gly Glu Val Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Trp Ile Gln Gly Val Lys Gly Gly Ser Pro 65 70 75 80 Ser Ala Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 95 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 95 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Gln Gly Val Ala Arg Ala Phe Asp Ser Phe 20 25 30 Leu Ile Thr Tyr Arg Glu Gln Ile Phe Ala Gly Glu Val Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Trp Ile Gln Gly Val Lys Gly Gly Ser Pro 65 70 75 80 Ser Ala Pro Leu Ser Ala Glu Phe Thr Thr 85 90 <210> 96 <211> 91 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 96 Met Ser Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu 1 5 10 15 Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser 20 25 30 Phe Pro Ile Ala Tyr Leu Glu Val Phe Tyr Glu Gly Glu Ala Ile Val 35 40 45 Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys 50 55 60 Pro Gly Thr Glu Tyr Gln Val Pro Ile Glu Gly Val Lys Gly Gly Ala 65 70 75 80 Met Ser Leu Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 97 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 97 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 His Ile Trp Tyr Glu Glu Glu Thr Thr Ile Gly Glu Ala Ile Tyr Leu 35 40 45 His Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Glu Val His Ile Thr Gly Val Lys Gly Gly Pro Tyr 65 70 75 80 Ser Arg Pro Leu Phe Ala Asn Phe Thr Thr 85 90 <210> 98 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 98 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Gly Ile Ala Tyr Asp Glu Trp Pro Glu Phe Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Asp Thr Glu Tyr Ile Val Glu Ile Tyr Gly Val Lys Gly Gly Trp Phe 65 70 75 80 Ser Trp Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 99 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 99 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Pro Tyr Ala Glu Pro Ser Pro Thr Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly His Leu 65 70 75 80 Ser Asp Pro Leu Ser Val Ile Phe Thr Thr 85 90 <210> 100 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 100 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Trp Tyr Glu Glu Val Met Tyr Leu Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Pro Ile Pro Gly Val Lys Gly Gly His Ser 65 70 75 80 Ser Pro Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 101 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 101 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 His Ile Leu Tyr Glu Glu Leu Phe Leu Val Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Lys Val Pro Ile Ser Gly Val Lys Gly Gly Pro Val 65 70 75 80 Ser Arg Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 102 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 102 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Gln Gly Val Ala Arg Ala Phe Asp Ser Phe 20 25 30 Leu Ile Thr Tyr Arg Glu Gln Ile Phe Ala Gly Glu Val Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Pro Val Trp Ile Gln Gly Val Lys Gly Gly Ser Pro 65 70 75 80 Ser Ala Pro Leu Ser Ala Glu Phe Thr Thr 85 90 <210> 103 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 103 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 His Ile Val Tyr His Glu Pro Arg Pro Ser Gly Glu Ala Ile Trp Leu 35 40 45 His Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Glu Val Gly Ile Val Ser Val Lys Gly Gly Asp Leu 65 70 75 80 Ser Val Pro Leu Val Ala Phe Phe Thr Thr 85 90 <210> 104 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 104 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Ser Leu 35 40 45 Leu Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Tyr Ala Val Phe Thr Thr 85 90 <210> 105 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 105 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Phe Leu 35 40 45 Val Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu His Ala Asn Phe Thr Thr 85 90 <210> 106 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 106 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Leu Leu 35 40 45 Asp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Tyr Ala Ser Phe Thr Thr 85 90 <210> 107 <211> 91 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 107 Met Ser Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu 1 5 10 15 Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser 20 25 30 Phe Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Ser 35 40 45 Leu Tyr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys 50 55 60 Pro Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu 65 70 75 80 Leu Ser Ser Pro Leu Ser Ala Ile Ser Thr Thr 85 90 <210> 108 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 108 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Gln Leu 35 40 45 Arg Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Met Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 109 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 109 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 His Ile Ser Tyr Glu Glu Asp Tyr Thr Phe Gly Glu Ala Ile Tyr Leu 35 40 45 Arg Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Arg Val Val Ile Gly Gly Val Lys Gly Gly Trp Phe 65 70 75 80 Ser Glu Pro Leu Leu Ala Ala Phe Thr Thr 85 90 <210> 110 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 110 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Tyr Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Tyr Pro Leu Asp Ala Ser Phe Thr Thr 85 90 <210> 111 <211> 93 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 111 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Asp Leu 35 40 45 Gly Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Met Pro Leu Asp Pro Leu Glu Ala Tyr Phe Thr Thr 85 90 <210> 112 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 112 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Leu Leu 35 40 45 Leu Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 113 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 113 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Asn Leu 35 40 45 Gln Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Val Ala Phe Phe Thr Thr 85 90 <210> 114 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 114 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Thr Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Ser Leu 35 40 45 Gln Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Ser Pro Leu Phe Ala Val Phe Thr Thr 85 90 <210> 115 <211> 87 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 115 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Glu Leu 35 40 45 His Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Phe Thr Thr 85 <210> 116 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 116 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gln Leu 35 40 45 Val Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 117 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 117 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Thr Leu 35 40 45 Asp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 118 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 118 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Trp Leu 35 40 45 Val Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Val Ala Ser Phe Thr Thr 85 90 <210> 119 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 119 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Asn Leu 35 40 45 Asp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Val Ala Glu Phe Thr Thr 85 90 <210> 120 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 120 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile His Leu 35 40 45 Ser Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Val Ala Ile Phe Thr Thr 85 90 <210> 121 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 121 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Ala Leu 35 40 45 Trp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Met Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 122 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 122 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Ile Leu 35 40 45 Val Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala His Phe Thr Thr 85 90 <210> 123 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 123 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Gln Leu 35 40 45 Trp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser His Pro Leu Gly Ala Val Phe Thr Thr 85 90 <210> 124 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 124 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gln Leu 35 40 45 His Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Leu Ala Ser Phe Thr Thr 85 90 <210> 125 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 125 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Ala Leu 35 40 45 His Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Val Ala Phe Phe Thr Thr 85 90 <210> 126 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 126 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile His Leu 35 40 45 His Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Ile Pro Leu His Ala Asn Phe Thr Thr 85 90 <210> 127 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 127 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Phe Leu 35 40 45 Gly Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 128 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 128 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Arg Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ile Ala Ser Phe Thr Thr 85 90 <210> 129 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 129 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Asn Leu 35 40 45 Trp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Asp Ala Ser Phe Thr Thr 85 90 <210> 130 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 130 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Val Ile Glu Tyr Phe Glu Trp Thr Leu Asn Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Gln Ile Tyr Gly Val Lys Gly Gly Cys Leu 65 70 75 80 Ser Arg Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 131 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 131 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile His Leu 35 40 45 Trp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ile Ala His Phe Thr Thr 85 90 <210> 132 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 132 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Pro Tyr Ala Glu Pro Ser Pro Thr Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala His Phe Thr Thr 85 90 <210> 133 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 133 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Tyr Leu 35 40 45 Tyr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Asp Ala Phe Phe Thr Thr 85 90 <210> 134 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 134 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gly Leu 35 40 45 Gln Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 135 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 135 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gln Leu 35 40 45 Ala Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu His Ala Phe Phe Thr Thr 85 90 <210> 136 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 136 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Trp Leu 35 40 45 His Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Ile Pro Leu Ile Ala Ile Phe Thr Thr 85 90 <210> 137 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 137 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Asp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Val Ala Glu Phe Thr Thr 85 90 <210> 138 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 138 Met Leu Pro Thr Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gln Leu 35 40 45 Arg Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu His Ala Ser Phe Thr Thr 85 90 <210> 139 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 139 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Gln Leu 35 40 45 Gly Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser His Pro Leu Asn Ala Asn Phe Thr Thr 85 90 <210> 140 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 140 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Gln Leu 35 40 45 Glu Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Met Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 141 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 141 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Phe Leu 35 40 45 Gly Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ile Ala Phe Phe Thr Thr 85 90 <210> 142 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 142 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Gly Leu 35 40 45 Gln Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser His Pro Leu Lys Ala Gln Phe Thr Thr 85 90 <210> 143 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 143 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Leu Leu 35 40 45 Phe Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Val Ala His Phe Thr Thr 85 90 <210> 144 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 144 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gly Leu 35 40 45 Tyr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Gly Ala Phe Phe Thr Thr 85 90 <210> 145 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 145 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Leu Leu 35 40 45 Gln Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Thr Ala Ile Phe Thr Thr 85 90 <210> 146 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 146 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Thr Leu 35 40 45 His Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 147 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 147 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Glu Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Asp Ala His Phe Thr Thr 85 90 <210> 148 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 148 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Ala Leu 35 40 45 His Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Arg Ala Val Phe Thr Thr 85 90 <210> 149 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 149 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gln Leu 35 40 45 Trp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 150 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 150 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Arg Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Ile Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 151 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 151 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Gln Leu 35 40 45 Trp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Arg Pro Leu Gln Ala His Phe Thr Thr 85 90 <210> 152 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 152 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Thr Leu 35 40 45 Asp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Tyr Ala Phe Phe Thr Thr 85 90 <210> 153 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 153 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Ala Leu 35 40 45 His Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 154 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 154 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gly Leu 35 40 45 Trp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ile Ala His Phe Thr Thr 85 90 <210> 155 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 155 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Trp Leu 35 40 45 Val Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu His Ala Arg Phe Thr Thr 85 90 <210> 156 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 156 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Phe Leu 35 40 45 Gln Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ala Ala Val Phe Thr Thr 85 90 <210> 157 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 157 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Leu Leu 35 40 45 His Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Ser Thr Thr 85 90 <210> 158 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 158 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Ile Leu 35 40 45 Gln Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Val Phe Thr Thr 85 90 <210> 159 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 159 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Tyr Leu 35 40 45 Lys Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Val Ala His Phe Thr Thr 85 90 <210> 160 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 160 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Leu Ala Tyr Phe Thr Thr 85 90 <210> 161 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 161 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Ile Leu 35 40 45 His Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Glu Ala Lys Phe Thr Thr 85 90 <210> 162 <211> 89 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 162 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Lys Leu 35 40 45 Glu Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ala Ile Phe Thr Thr 85 <210> 163 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 163 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Tyr Leu 35 40 45 Glu Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Phe Pro Leu Lys Ala Ala Phe Thr Thr 85 90 <210> 164 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 164 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Ile Leu 35 40 45 Arg Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Val Ala Ile Phe Thr Thr 85 90 <210> 165 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 165 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Gln Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ala Ala Trp Phe Thr Thr 85 90 <210> 166 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 166 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Phe Leu 35 40 45 Gln Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Asn Ala Phe Phe Thr Thr 85 90 <210> 167 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 167 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Ile Leu 35 40 45 Gly Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu His Ala Tyr Ser Thr Thr 85 90 <210> 168 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 168 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Leu Leu 35 40 45 Asp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 169 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 169 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Leu Leu 35 40 45 Leu Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Val Phe Thr Thr 85 90 <210> 170 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 170 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile His Leu 35 40 45 Leu Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Leu Ala His Phe Thr Thr 85 90 <210> 171 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 171 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gln Leu 35 40 45 Trp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Asp Ala Tyr Phe Thr Thr 85 90 <210> 172 <211> 89 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 172 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Met Pro Leu Ala Ser Phe Thr Thr 85 <210> 173 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 173 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 His Ile Val Tyr His Glu Pro Arg Pro Ser Gly Glu Ala Ile His Leu 35 40 45 Gln Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Tyr Pro Leu Ser Ala Phe Phe Thr Thr 85 90 <210> 174 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 174 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Gln Leu 35 40 45 Trp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Met Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 175 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 175 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Arg Ile Ser Tyr Cys Glu Thr Phe Tyr His Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ile Ala Lys Phe Thr Thr 85 90 <210> 176 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 176 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Trp Leu 35 40 45 Lys Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Gln Ala Asn Phe Thr Thr 85 90 <210> 177 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 177 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Trp Leu 35 40 45 Lys Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Gln Ala Asn Phe Thr Thr 85 90 <210> 178 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 178 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gln Leu 35 40 45 Gln Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Val Thr Thr 85 90 <210> 179 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 179 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Pro Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Phe Phe Thr Thr 85 90 <210> 180 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 180 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Ala Leu 35 40 45 Leu Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Val Ala Gln Phe Thr Thr 85 90 <210> 181 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 181 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Ile Leu 35 40 45 His Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Glu Ala Lys Phe Thr Thr 85 90 <210> 182 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 182 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Asp Leu 35 40 45 His Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu His Ala Leu Phe Thr Thr 85 90 <210> 183 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 183 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Leu Leu 35 40 45 Asp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Met Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 184 <211> 88 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 184 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Asp Leu 35 40 45 Ala Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Phe Thr Thr 85 <210> 185 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 185 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Tyr Leu 35 40 45 Gly Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Arg Ala Lys Phe Thr Thr 85 90 <210> 186 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 186 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gln Leu 35 40 45 Gly Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 187 <211> 88 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 187 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Ser Leu 35 40 45 Leu Val Pro Asp Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Met Pro Leu Lys Phe Thr Thr 85 <210> 188 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 188 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gly Leu 35 40 45 Gly Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Asp Ala Ser Phe Thr Thr 85 90 <210> 189 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 189 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gln Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Pro Lys Pro 50 55 60 Gly Thr Glu Tyr Trp Val Leu Ile Gln Gly Val Lys Gly Gly Gly Ser 65 70 75 80 Ser Val Pro Leu Val Ala Tyr Phe Thr Thr 85 90 <210> 190 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 190 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Ser Leu 35 40 45 Asp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Glu Ala Ser Phe Thr Thr 85 90 <210> 191 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 191 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Ile Leu 35 40 45 Ala Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Leu Pro Leu Val Ala Ser Phe Thr Thr 85 90 <210> 192 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 192 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Asp Ile Gly Tyr Thr Glu Tyr Gly Gly Tyr Gly Glu Ala Ile Tyr Leu 35 40 45 Ser Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Trp Val Leu Ile Gln Gly Val Lys Gly Gly Gly Ser 65 70 75 80 Ser Val Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 193 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 193 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Ser Leu 35 40 45 Ser Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ile Ala Asn Phe Thr Thr 85 90 <210> 194 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 194 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Ala Leu 35 40 45 Leu Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Val Thr Thr 85 90 <210> 195 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 195 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Ile Leu 35 40 45 Asp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ser Ile Phe Thr Thr 85 90 <210> 196 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 196 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Trp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Arg Ala Ser Phe Thr Thr 85 90 <210> 197 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 197 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Lys Leu 35 40 45 Asp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Val Ala Phe Phe Thr Thr 85 90 <210> 198 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 198 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Ile Leu 35 40 45 Glu Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Val Ala Tyr Phe Thr Thr 85 90 <210> 199 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 199 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile His Leu 35 40 45 Trp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu His Ala Asp Phe Thr Thr 85 90 <210> 200 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 200 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Trp Leu 35 40 45 Glu Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Val Ala Asp Phe Thr Thr 85 90 <210> 201 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 201 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Ser Leu 35 40 45 Trp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Leu Ala His Phe Thr Thr 85 90 <210> 202 <211> 89 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 202 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Asp Ile Gly Tyr Thr Glu Tyr Gly Gly Tyr Gly Glu Ala Ile Leu His 35 40 45 Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly 50 55 60 Thr Glu Tyr Trp Val Leu Ile Gln Gly Val Lys Gly Gly Gly Ser Ser 65 70 75 80 Val Pro Leu Ser Ala Ile Phe Thr Thr 85 <210> 203 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 203 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Val Leu 35 40 45 Leu Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Val Pro Leu Ala Ala Phe Phe Thr Thr 85 90 <210> 204 <211> 85 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 204 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Leu Leu 35 40 45 Trp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Gln Phe Thr Thr 85 <210> 205 <211> 93 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 205 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Leu Leu 35 40 45 Gly Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Met Pro Leu His Pro Leu Val Ala Leu Phe Thr Thr 85 90 <210> 206 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 206 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gly Leu 35 40 45 Asp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 207 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 207 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile His Leu 35 40 45 Ser Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ala Ala Tyr Phe Thr Thr 85 90 <210> 208 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 208 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Val Leu 35 40 45 Ala Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Tyr Pro Leu Val Ala Ala Phe Thr Thr 85 90 <210> 209 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 209 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Leu Leu 35 40 45 Gln Val Pro Gly Ser Cys Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Thr Ala Ile Phe Thr Thr 85 90 <210> 210 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 210 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Asn Leu 35 40 45 Gln Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Phe Pro Leu Ser Ala Val Phe Thr Thr 85 90 <210> 211 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 211 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gln Leu 35 40 45 His Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Val Ala Ile Phe Thr Thr 85 90 <210> 212 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 212 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Trp Leu 35 40 45 Ala Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu His Ala Gln Phe Thr Thr 85 90 <210> 213 <211> 87 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 213 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Leu Leu 35 40 45 Gly Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Phe Thr Thr 85 <210> 214 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 214 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gly Leu 35 40 45 Gln Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Cys Ala Glu Phe Thr Thr 85 90 <210> 215 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 215 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Trp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ile Ala Glu Phe Thr Thr 85 90 <210> 216 <211> 88 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 216 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Ser Leu 35 40 45 Ser Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Pro Lys Phe Thr Thr 85 <210> 217 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 217 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Ile Leu 35 40 45 Glu Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Arg Ala Val Phe Thr Thr 85 90 <210> 218 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 218 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile His Leu 35 40 45 Val Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 219 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 219 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Ser Leu 35 40 45 Lys Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Glu Ala Ile Phe Thr Thr 85 90 <210> 220 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 220 Met Leu Pro Ala Pro Lys Asn Pro Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile His Leu 35 40 45 Leu Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Lys Arg Leu Ser Pro Pro Val Val Thr Ile Thr Ile 85 90 95 Thr Met Ala Val Cys Arg Lys Pro Val Ala Glu Asn Leu Ser Gln Thr 100 105 110 Leu Ser <210> 221 <211> 89 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 221 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Phe Leu 35 40 45 Asp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Pro Leu Thr Ala Phe Phe Thr Thr 85 <210> 222 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 222 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Val Leu 35 40 45 Asp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser His Pro Leu Ala Ala Ala Phe Thr Thr 85 90 <210> 223 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 223 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Gly Leu 35 40 45 Ala Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Val Pro Leu Gln Ala Asn Phe Thr Thr 85 90 <210> 224 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 224 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Leu Leu 35 40 45 Arg Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Val Ala Glu Phe Thr Thr 85 90 <210> 225 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 225 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Leu Leu 35 40 45 Gln Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Ser Phe Thr Thr 85 90 <210> 226 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 226 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gly Leu 35 40 45 His Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Thr Ala Ser Phe Thr Thr 85 90 <210> 227 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 227 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gly Leu 35 40 45 Arg Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 228 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 228 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Arg Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ala Ala Ser Phe Thr Thr 85 90 <210> 229 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 229 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gln Leu 35 40 45 Leu Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Val Ala His Phe Thr Thr 85 90 <210> 230 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 230 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Trp Leu 35 40 45 Leu Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Val Ala Phe Phe Thr Thr 85 90 <210> 231 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 231 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile His Leu 35 40 45 Tyr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Asp Pro Leu Asp Ala Val Phe Thr Thr 85 90 <210> 232 <211> 85 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 232 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Tyr Leu 35 40 45 Asp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Thr Phe Thr Thr 85 <210> 233 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 233 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gln Leu 35 40 45 Phe Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Lys Ala Tyr Phe Thr Thr 85 90 <210> 234 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 234 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Val Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 235 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 235 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Gln Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Leu Pro Leu Ser Ala Asp Phe Thr Thr 85 90 <210> 236 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 236 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Leu Leu 35 40 45 Gln Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Asp Ala Glu Phe Thr Thr 85 90 <210> 237 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 237 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Ala Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Tyr Ala Ser Phe Thr Thr 85 90 <210> 238 <211> 88 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 238 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Thr Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Arg Leu 35 40 45 Gln Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Gly Phe Thr Thr 85 <210> 239 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 239 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gln Leu 35 40 45 Val Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Tyr Ala Ile Phe Thr Thr 85 90 <210> 240 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 240 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Ser Leu 35 40 45 Ser Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu His Ala Lys Phe Thr Thr 85 90 <210> 241 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 241 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile His Leu 35 40 45 Gly Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Ile Pro Leu Phe Ala Ser Phe Thr Thr 85 90 <210> 242 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 242 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gln Leu 35 40 45 Leu Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Tyr Ala Ala Phe Thr Thr 85 90 <210> 243 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 243 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile His Leu 35 40 45 Ala Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Val Pro Leu Ala Ala Val Phe Thr Thr 85 90 <210> 244 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 244 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Ser Leu 35 40 45 Gln Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Gly Ala His Phe Thr Thr 85 90 <210> 245 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 245 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Ala Leu 35 40 45 Trp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Val Ala Ser Phe Thr Thr 85 90 <210> 246 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 246 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gln Leu 35 40 45 His Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Tyr Ala Phe Phe Thr Thr 85 90 <210> 247 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 247 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Leu Leu 35 40 45 His Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Arg Ala Ser Phe Thr Thr 85 90 <210> 248 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 248 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Trp Leu 35 40 45 Gly Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu His Ala Thr Phe Thr Thr 85 90 <210> 249 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 249 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Glu Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu His Ala Asn Phe Thr Thr 85 90 <210> 250 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 250 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Leu Leu 35 40 45 Arg Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Tyr Ala Lys Phe Thr Thr 85 90 <210> 251 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 251 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Gly Leu 35 40 45 Trp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Asp Pro Leu Gln Ala Val Phe Thr Thr 85 90 <210> 252 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 252 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 His Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Asp Ala Phe Phe Thr Thr 85 90 <210> 253 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 253 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Ile Leu 35 40 45 His Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Asp Ala Tyr Phe Thr Thr 85 90 <210> 254 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 254 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Leu Leu 35 40 45 Ala Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Lys Phe Thr Thr 85 90 <210> 255 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 255 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Leu Leu 35 40 45 Phe Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Thr Pro Leu Ser Ala Ser Phe Thr Thr 85 90 <210> 256 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 256 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gln Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu His Ala Tyr Phe Thr Thr 85 90 <210> 257 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 257 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gln Leu 35 40 45 Gly Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Arg Ala Tyr Phe Thr Thr 85 90 <210> 258 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 258 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Leu Leu 35 40 45 Glu Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Val Ala Phe Phe Thr Thr 85 90 <210> 259 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 259 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gln Leu 35 40 45 Gly Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Leu Ala Val Phe Thr Thr 85 90 <210> 260 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 260 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile His Leu 35 40 45 Arg Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Met Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 261 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 261 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Leu Leu 35 40 45 Gln Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ile Ala Lys Phe Thr Thr 85 90 <210> 262 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 262 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 His Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Gln Ala Ile Phe Thr Thr 85 90 <210> 263 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 263 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Ala Leu 35 40 45 Val Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ala Ala Asn Phe Thr Thr 85 90 <210> 264 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 264 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Asn Leu 35 40 45 Ser Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Asp Ala Tyr Phe Thr Thr 85 90 <210> 265 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 265 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Glu Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Thr Ala Ser Phe Thr Thr 85 90 <210> 266 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 266 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Arg Leu 35 40 45 Gln Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Gly Ala Ser Phe Thr Thr 85 90 <210> 267 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 267 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Gly Leu 35 40 45 Trp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Val Ala Tyr Phe Thr Thr 85 90 <210> 268 <211> 87 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 268 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Tyr Leu 35 40 45 Glu Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Phe Thr Thr 85 <210> 269 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 269 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Trp Leu 35 40 45 Asp Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Asp Ala Tyr Phe Thr Thr 85 90 <210> 270 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 270 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Ala Ile Glu Tyr Cys Glu Thr Lys Met Cys Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Arg Val Pro Ile Pro Gly Val Lys Gly Gly Thr Ala 65 70 75 80 Ser Leu Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 271 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 271 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Tyr Tyr Ile Glu Ser Tyr Pro Ala Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Trp Val Gly Ile Asp Gly Val Lys Gly Gly Arg Trp 65 70 75 80 Ser Thr Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 272 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 272 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Tyr Tyr Ile Glu Ser Tyr Pro Ala Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Cys Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Trp Val Gly Ile Asp Gly Val Lys Gly Gly Arg Trp 65 70 75 80 Ser Thr Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 273 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <220> <221> MOD_RES <222> (33)..(33) <223> D, F, Y, or H <220> <221> MOD_RES <222> (35)..(35) <223> Y, G, A, or V <220> <221> MOD_RES <222> (37)..(37) <223> I, T, L, A, or H <220> <221> MOD_RES <222> (39)..(39) <223> S, Y or P <220> <221> MOD_RES <222> (40)..(40) <223> Y, G, Q, or R <220> <221> MOD_RES <222> (41)..(41) <223> G or P <220> <221> MOD_RES <222> (42)..(42) <223> A, Y, P, D, or S <220> <221> MOD_RES <222> (47)..(47) <223> A, C, D, E, F, G, H, I, K, L, N, Q, R, S, T, V, W, or Y <220> <221> MOD_RES <222> (49)..(49) <223> A, C, D, E, F, G, H, I, K, L, N, Q, R, S, T, V, W, or Y <220> <221> MOD_RES <222> (69)..(69) <223> W, N, S, or E <220> <221> MOD_RES <222> (71)..(71) <223> L, Y, or G <220> <221> MOD_RES <222> (73)..(73) <223> D, Q, H, or V <220> <221> MOD_RES <222> (74)..(74) <223> G or S <220> <221> MOD_RES <222> (79)..(79) <223> R, G, F, L, or D <220> <221> MOD_RES <222> (80)..(80) <223> W, S, P, or L <220> <221> MOD_RES <222> (82)..(82) <223> T, V, M, or S <220> <221> MOD_RES <222> (85)..(85) <223> A, C, D, E, F, G, H, I, K, L, N, Q, R, S, T, V, W, or Y <220> <221> MOD_RES <222> (87)..(87) <223> A, C, D, E, F, G, H, I, K, L, N, Q, R, S, T, V, W, or Y <400> 273 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Xaa Ile Xaa Tyr Xaa Glu Xaa Xaa 35 40 45 Xaa Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Xaa Val 65 70 75 80 Ser Xaa Pro Leu Xaa Ala Xaa Phe Thr Thr 85 90 <210> 274 <211> 291 <212> PRT <213> Homo sapiens <400> 274 Met Thr Lys Glu Tyr Gln Asp Leu Gln His Leu Asp Asn Glu Glu Ser 1 5 10 15 Asp His His Gln Leu Arg Lys Gly Pro Pro Pro Pro Gln Pro Leu Leu 20 25 30 Gln Arg Leu Cys Ser Gly Pro Arg Leu Leu Leu Leu Ser Leu Gly Leu 35 40 45 Ser Leu Leu Leu Leu Val Val Val Cys Val Ile Gly Ser Gln Asn Ser 50 55 60 Gln Leu Gln Glu Glu Leu Arg Gly Leu Arg Glu Thr Phe Ser Asn Phe 65 70 75 80 Thr Ala Ser Thr Glu Ala Gln Val Lys Gly Leu Ser Thr Gln Gly Gly 85 90 95 Asn Val Gly Arg Lys Met Lys Ser Leu Glu Ser Gln Leu Glu Lys Gln 100 105 110 Gln Lys Asp Leu Ser Glu Asp His Ser Ser Leu Leu Leu His Val Lys 115 120 125 Gln Phe Val Ser Asp Leu Arg Ser Leu Ser Cys Gln Met Ala Ala Leu 130 135 140 Gln Gly Asn Gly Ser Glu Arg Thr Cys Cys Pro Val Asn Trp Val Glu 145 150 155 160 His Glu Arg Ser Cys Tyr Trp Phe Ser Arg Ser Gly Lys Ala Trp Ala 165 170 175 Asp Ala Asp Asn Tyr Cys Arg Leu Glu Asp Ala His Leu Val Val Val 180 185 190 Thr Ser Trp Glu Glu Gln Lys Phe Val Gln His His Ile Gly Pro Val 195 200 205 Asn Thr Trp Met Gly Leu His Asp Gln Asn Gly Pro Trp Lys Trp Val 210 215 220 Asp Gly Thr Asp Tyr Glu Thr Gly Phe Lys Asn Trp Arg Pro Glu Gln 225 230 235 240 Pro Asp Asp Trp Tyr Gly His Gly Leu Gly Gly Gly Glu Asp Cys Ala 245 250 255 His Phe Thr Asp Asp Gly Arg Trp Asn Asp Asp Val Cys Gln Arg Pro 260 265 270 Tyr Arg Trp Val Cys Glu Thr Glu Leu Asp Lys Ala Ser Gln Glu Pro 275 280 285 Pro Leu Leu 290 <210> 275 <211> 230 <212> PRT <213> Homo sapiens <400> 275 Gln Asn Ser Gln Leu Gln Glu Glu Leu Arg Gly Leu Arg Glu Thr Phe 1 5 10 15 Ser Asn Phe Thr Ala Ser Thr Glu Ala Gln Val Lys Gly Leu Ser Thr 20 25 30 Gln Gly Gly Asn Val Gly Arg Lys Met Lys Ser Leu Glu Ser Gln Leu 35 40 45 Glu Lys Gln Gln Lys Asp Leu Ser Glu Asp His Ser Ser Leu Leu Leu 50 55 60 His Val Lys Gln Phe Val Ser Asp Leu Arg Ser Leu Ser Cys Gln Met 65 70 75 80 Ala Ala Leu Gln Gly Asn Gly Ser Glu Arg Thr Cys Cys Pro Val Asn 85 90 95 Trp Val Glu His Glu Arg Ser Cys Tyr Trp Phe Ser Arg Ser Gly Lys 100 105 110 Ala Trp Ala Asp Ala Asp Asn Tyr Cys Arg Leu Glu Asp Ala His Leu 115 120 125 Val Val Val Thr Ser Trp Glu Glu Gln Lys Phe Val Gln His His Ile 130 135 140 Gly Pro Val Asn Thr Trp Met Gly Leu His Asp Gln Asn Gly Pro Trp 145 150 155 160 Lys Trp Val Asp Gly Thr Asp Tyr Glu Thr Gly Phe Lys Asn Trp Arg 165 170 175 Pro Glu Gln Pro Asp Asp Trp Tyr Gly His Gly Leu Gly Gly Gly Glu 180 185 190 Asp Cys Ala His Phe Thr Asp Asp Gly Arg Trp Asn Asp Asp Val Cys 195 200 205 Gln Arg Pro Tyr Arg Trp Val Cys Glu Thr Glu Leu Asp Lys Ala Ser 210 215 220 Gln Glu Pro Pro Leu Leu 225 230 <210> 276 <211> 89 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 276 Leu Pro Ala Pro Lys Asn Leu Val Val Ser Glu Val Thr Glu Asp Ser 1 5 10 15 Leu Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Leu 20 25 30 Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Asn Leu Thr 35 40 45 Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly 50 55 60 Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val Lys Gly Gly His Arg Ser 65 70 75 80 Asn Pro Leu Ser Ala Glu Phe Thr Thr 85 <210> 277 <211> 89 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 277 Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser 1 5 10 15 Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Leu 20 25 30 Ile Gln Tyr Gln Glu Ser Glu Lys Val Gly Glu Ala Ile Val Leu Thr 35 40 45 Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly 50 55 60 Thr Glu Tyr Thr Val Ser Ile Tyr Gly Val Lys Gly Gly His Arg Ser 65 70 75 80 Asn Pro Leu Ser Ala Ile Phe Thr Thr 85 <210> 278 <211> 4 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 278 Gly Ser Gly Ser One <210> 279 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 279 Gly Gly Gly Ser Gly Gly Gly Ser 1 5 <210> 280 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <221> SITE <222> (1)..(25) <223> This sequence may encompass 1-5 “Gly Gly Gly Gly Ser” repeating units <400> 280 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15 Gly Gly Gly Ser Gly Gly Gly Gly Ser 20 25 <210> 281 <211> 4 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 281 Ala Pro Ala Pro One <210> 282 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 282 Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro 1 5 10 <210> 283 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 283 Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro 1 5 10 15 Ala Pro Ala Pro 20 <210> 284 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 284 Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro 1 5 10 15 Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro 20 25 30 Ala Pro Ala Pro Ala Pro Ala Pro 35 40 <210> 285 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 285 Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys 1 5 10 15 Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala Ala Ala 20 25 <210> 286 <211> 19 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 286 ucucguggcc uuaaugaaa 19 <210> 287 <211> 20 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 287 uucauuaagg ccacgagauu 20 <210> 288 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 288 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Tyr Ile Ala Tyr Ala Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Ser Val Leu Ile His Gly Val Lys Gly Gly Leu Leu 65 70 75 80 Ser Ser Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 289 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 289 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Met Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 290 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 290 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 His Ile Val Tyr His Glu Pro Arg Pro Ser Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Glu Val Gly Ile Val Ser Val Lys Gly Gly Asp Leu 65 70 75 80 Ser Val Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 291 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 291 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Asp Ile Gly Tyr Thr Glu Tyr Gly Gly Tyr Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Trp Val Leu Ile Gln Gly Val Lys Gly Gly Gly Ser 65 70 75 80 Ser Val Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 292 <211> 189 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 292 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Ala Ile Val Tyr His Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Cys Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Glu Val Val Ile Leu Gly Val Lys Gly Gly Val His 65 70 75 80 Ser Tyr Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro Ala Pro Ala Pro 85 90 95 Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val 100 105 110 Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe 115 120 125 Asp Ser Phe Ala Ile Val Tyr His Glu Pro Arg Pro Asp Gly Glu Ala 130 135 140 Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly 145 150 155 160 Leu Lys Pro Gly Thr Glu Tyr Glu Val Val Ile Leu Gly Val Lys Gly 165 170 175 Gly Val His Ser Tyr Pro Leu Ser Ala Ile Phe Thr Thr 180 185 <210> 293 <211> 199 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 293 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Ala Ile Val Tyr His Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Cys Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Glu Val Val Ile Leu Gly Val Lys Gly Gly Val His 65 70 75 80 Ser Tyr Pro Leu Ser Ala Ile Phe Thr Thr Gly Gly Gly Gly Ser Gly 85 90 95 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Leu Pro 100 105 110 Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg 115 120 125 Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Ala Ile Val 130 135 140 Tyr His Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu Thr Val Pro 145 150 155 160 Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu 165 170 175 Tyr Glu Val Val Ile Leu Gly Val Lys Gly Gly Val His Ser Tyr Pro 180 185 190 Leu Ser Ala Ile Phe Thr Thr 195 <210> 294 <211> 199 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 294 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Ala Ile Val Tyr His Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Cys Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Glu Val Val Ile Leu Gly Val Lys Gly Gly Val His 65 70 75 80 Ser Tyr Pro Leu Ser Ala Ile Phe Thr Thr Glu Ala Ala Ala Lys Glu 85 90 95 Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Leu Pro 100 105 110 Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg 115 120 125 Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Ala Ile Val 130 135 140 Tyr His Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu Thr Val Pro 145 150 155 160 Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu 165 170 175 Tyr Glu Val Val Ile Leu Gly Val Lys Gly Gly Val His Ser Tyr Pro 180 185 190 Leu Ser Ala Ile Phe Thr Thr 195 <210> 295 <211> 184 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 295 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Ala Ile Val Tyr His Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Cys Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Glu Val Val Ile Leu Gly Val Lys Gly Gly Val His 65 70 75 80 Ser Tyr Pro Leu Ser Ala Ile Phe Thr Thr Glu Ala Ala Ala Lys Leu 85 90 95 Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser Ala 100 105 110 Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Ala Ile 115 120 125 Val Tyr His Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu Thr Val 130 135 140 Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr 145 150 155 160 Glu Tyr Glu Val Val Ile Leu Gly Val Lys Gly Gly Val His Ser Tyr 165 170 175 Pro Leu Ser Ala Ile Phe Thr Thr 180 <210> 296 <211> 189 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 296 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Lys Ile Glu Tyr Phe Glu Tyr Val Gly Tyr Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Cys Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Tyr Val Ala Ile Tyr Gly Val Lys Gly Gly Trp Tyr 65 70 75 80 Ser Arg Pro Leu Ser Ala Ile Phe Thr Thr Ala Pro Ala Pro Ala Pro 85 90 95 Ala Pro Ala Pro Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val 100 105 110 Thr Glu Asp Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe 115 120 125 Asp Ser Phe Lys Ile Glu Tyr Phe Glu Tyr Val Gly Tyr Gly Glu Ala 130 135 140 Ile Val Leu Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly 145 150 155 160 Leu Lys Pro Gly Thr Glu Tyr Tyr Val Ala Ile Tyr Gly Val Lys Gly 165 170 175 Gly Trp Tyr Ser Arg Pro Leu Ser Ala Ile Phe Thr Thr 180 185 <210> 297 <211> 199 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 297 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Lys Ile Glu Tyr Phe Glu Tyr Val Gly Tyr Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Cys Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Tyr Val Ala Ile Tyr Gly Val Lys Gly Gly Trp Tyr 65 70 75 80 Ser Arg Pro Leu Ser Ala Ile Phe Thr Thr Gly Gly Gly Gly Ser Gly 85 90 95 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Leu Pro 100 105 110 Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg 115 120 125 Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Lys Ile Glu 130 135 140 Tyr Phe Glu Tyr Val Gly Tyr Gly Glu Ala Ile Val Leu Thr Val Pro 145 150 155 160 Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu 165 170 175 Tyr Tyr Val Ala Ile Tyr Gly Val Lys Gly Gly Trp Tyr Ser Arg Pro 180 185 190 Leu Ser Ala Ile Phe Thr Thr 195 <210> 298 <211> 199 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 298 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Lys Ile Glu Tyr Phe Glu Tyr Val Gly Tyr Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Cys Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Tyr Val Ala Ile Tyr Gly Val Lys Gly Gly Trp Tyr 65 70 75 80 Ser Arg Pro Leu Ser Ala Ile Phe Thr Thr Glu Ala Ala Ala Lys Glu 85 90 95 Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Leu Pro 100 105 110 Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser Ala Arg 115 120 125 Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Lys Ile Glu 130 135 140 Tyr Phe Glu Tyr Val Gly Tyr Gly Glu Ala Ile Val Leu Thr Val Pro 145 150 155 160 Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr Glu 165 170 175 Tyr Tyr Val Ala Ile Tyr Gly Val Lys Gly Gly Trp Tyr Ser Arg Pro 180 185 190 Leu Ser Ala Ile Phe Thr Thr 195 <210> 299 <211> 184 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 299 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Lys Ile Glu Tyr Phe Glu Tyr Val Gly Tyr Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Cys Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Tyr Val Ala Ile Tyr Gly Val Lys Gly Gly Trp Tyr 65 70 75 80 Ser Arg Pro Leu Ser Ala Ile Phe Thr Thr Glu Ala Ala Ala Lys Leu 85 90 95 Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp Ser Ala 100 105 110 Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe Lys Ile 115 120 125 Glu Tyr Phe Glu Tyr Val Gly Tyr Gly Glu Ala Ile Val Leu Thr Val 130 135 140 Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro Gly Thr 145 150 155 160 Glu Tyr Tyr Val Ala Ile Tyr Gly Val Lys Gly Gly Trp Tyr Ser Arg 165 170 175 Pro Leu Ser Ala Ile Phe Thr Thr 180 <210>300 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 300 Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu 1 5 10 15 Ala Ala Ala Lys 20 <210> 301 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 301 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15 Gly Gly Gly Ser 20 <210> 302 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 302 Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro 1 5 10 <210> 303 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 303 Glu Ala Ala Ala Lys 1 5 <210> 304 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 304 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Ala Ile Val Tyr His Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Cys Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Glu Val Val Ile Leu Gly Val Lys Gly Gly Val His 65 70 75 80 Ser Tyr Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 305 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 305 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Ala Ile Val Tyr His Glu Pro Arg Pro Asp Gly Glu Ala Ile Val Leu 35 40 45 Thr Val Pro Gly Ser Glu Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Glu Val Val Ile Leu Gly Val Lys Gly Gly Val His 65 70 75 80 Ser Tyr Pro Leu Ser Ala Ile Phe Thr Thr 85 90 <210> 306 <211> 90 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 306 Met Leu Pro Ala Pro Lys Asn Leu Val Val Ser Arg Val Thr Glu Asp 1 5 10 15 Ser Ala Arg Leu Ser Trp Thr Ala Pro Asp Ala Ala Phe Asp Ser Phe 20 25 30 Phe Ile Gly Tyr Leu Glu Pro Gln Pro Pro Gly Glu Ala Ile His Leu 35 40 45 Gly Val Pro Gly Ser Cys Arg Ser Tyr Asp Leu Thr Gly Leu Lys Pro 50 55 60 Gly Thr Glu Tyr Asn Val Thr Ile Gln Gly Val Lys Gly Gly Phe Pro 65 70 75 80 Ser Ile Pro Leu Phe Ala Ser Phe Thr Thr 85 90 <210> 307 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <221> SITE <222> (1)..(25) <223> This sequence may encompass 1-5 “Glu Ala Ala Ala Lys” repeating units <400> 307 Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu 1 5 10 15 Ala Ala Ala Lys Glu Ala Ala Ala Lys 20 25 <210> 308 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 308 Gly Gly Gly Gly Ser 1 5 <210> 309 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic 6xHis tag <400> 309 His His His His His His 1 5 <210> 310 <211> 4 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <220> <221> MOD_RES <222> (4)..(4) <223> Citrulline <400> 310 Gly Gly Val Xaa One <210> 311 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <220> <221> SITE <222> (1)..(40) <223> This sequence may encompass 1-20 “Ala Pro” repeating units <400> 311 Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro 1 5 10 15 Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro 20 25 30 Ala Pro Ala Pro Ala Pro Ala Pro 35 40

Claims (53)

A polypeptide comprising an amino acid sequence that is at least 70%, 75%, 80%, 85% or 90% identical to the amino acid sequence of SEQ ID NO: 273. The polypeptide according to claim 1, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306. The polypeptide of claim 2, wherein the polypeptide comprises two of SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306. A polypeptide that binds human CD71 at a site on CD71 that does not compete with transferrin binding to CD71. The polypeptide of claim 4, wherein the polypeptide comprises an amino acid sequence that is at least 70%, 75%, 80%, 85% or 90% identical to the polypeptide having the sequence of SEQ ID NO: 273. The polypeptide of claim 4, wherein the polypeptide comprises the sequences of SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306. 7. The polypeptide of any one of claims 1 to 6, wherein the polypeptide is conjugated to a detectable label, oligonucleotide, therapeutic agent, or any combination thereof. 8. The polypeptide of claim 7, wherein the detectable label is a radioactive isotope, magnetic bead, metal bead, colloidal particle, fluorescent dye, electron-dense reagent, enzyme, biotin, digoxigenin or hapten. 9. The polypeptide according to claim 7 or 8, wherein the detectable label is auristatin, monomethyl auristatin phenylalanine, dolostatin, a chemotherapeutic agent, drug, growth inhibitor, toxin or radioisotope. The method of claim 7, wherein the therapeutic agent is a chemotherapeutic agent, drug, antibody, growth inhibitor, toxin, radioisotope, anti-tubulin agent, polynucleotide, siRNA molecule or sense or antisense strand thereof, antisense molecule or strand thereof, RNA. Molecule, DNA molecule, DNA minor groove binder, DNA replication inhibitor, alkylating agent, antibiotic, antifolate, antimetabolite, chemotherapy sensitizer, topoisomerase inhibitor or vinca alkaloid, polypeptide. 8. The method of claim 7, wherein the therapeutic agent modulates gene expression, RNA expression or levels, tubulin binding, DNA binding, topoisomerase inhibition, DNA cross-linking, chelation, spliceosome inhibition, NAMPT inhibition, or HDAC inhibition. A polypeptide that can cause more than one cytotoxic effect. 12. The polypeptide according to any one of claims 1 to 11, further comprising methionine at the N-terminus of the polypeptide. 13. The polypeptide of any one of claims 1 to 12, wherein the polypeptide is coupled to a half-life extending moiety. 14. The polypeptide of claim 13, wherein the half-life extending moiety is at least part of the Fc region of an albumin binding molecule, polyethylene glycol (PEG), albumin, an albumin variant, or an immunoglobulin. 15. The polypeptide of claim 14, wherein the albumin binding molecule is a second polypeptide that binds albumin or an albumin variant. An isolated polynucleotide encoding the polypeptide of any one of claims 1 to 15. A vector containing the polynucleotide of claim 16. A host cell containing the vector of claim 17. A method for producing a polypeptide that binds to CD71, comprising culturing the isolated host cell of claim 18 under conditions in which the polypeptide is expressed and purifying the polypeptide. A pharmaceutical composition comprising the polypeptide of any one of claims 1 to 15 and a pharmaceutically acceptable carrier. An anti-idiotypic antibody that binds to the polypeptide of any one of claims 1 to 15. A kit comprising the polypeptide of any one of claims 1 to 15. A method of treating cancer in a subject in need thereof, comprising comprising the polypeptides provided herein, such as SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306, with a therapeutic agent. A method comprising administering to the subject together. 24. The method of claim 23, wherein the cancer is brain cancer. A method of treating cancer in a subject in need thereof, comprising: SEQ ID NO: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299 or 304 to 306 conjugated with an antiviral agent, immune system modulator or nucleic acid molecule. A method comprising administering to the subject a polypeptide described herein, such as: 26. The method of claim 25, wherein the cancer disease is glioblastoma. A method for detecting CD71-expressing cancer cells in tumor tissue, comprising:
a) obtaining a sample of said tumor tissue from a subject; and
b) contacting the sample of tumor tissue with a polypeptide comprising the amino acid sequence of one of SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299 or 304 to 306, between CD71 and the polypeptide Detecting whether CD71 is expressed in the tumor tissue by detecting the binding of
Method, including. As a method of isolating CD71 expressing cells,
a) obtaining a sample from the subject;
b) contacting the sample with a polypeptide comprising the amino acid sequence of one of SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299 or 304 to 306, and
c) isolating cells bound to the polypeptide
Method, including. A method for detecting CD71-expressing cancer cells in tumor tissue, comprising:
a) conjugating a peptide containing one of the amino acid sequences of SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299 or 304 to 306 to a detectable label to form a conjugate;
b) administering the conjugate to the subject; and
c) Visualizing CD71-expressing cancer cells to which the conjugate is bound
Method, including. A method of treating a neurological condition and/or brain tumor, comprising administering to a subject the pharmaceutical composition of claim 20. 31. The method of claim 30, wherein the brain tumor is selected from the group consisting of non-malignant, benign and malignant brain tumors. 32. The method of claim 31, wherein the malignant brain tumor is astrocytoma, medulloblastoma, glioma, ependymoma, blastoma (pineal adenoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma or spinal cord cancer, such as nerve cancer. A method selected from the group consisting of fibromas, meningiomas, gliomas, and sarcomas. 32. The method of claim 31, wherein the brain tumor is a congenital tumor. 31. The method of claim 30, wherein the neurological condition is selected from the group consisting of stroke, diabetes, seizures, hypertensive encephalopathy, acquired immunodeficiency syndrome, traumatic brain injury, multiple sclerosis, Parkinson's disease (PD), and Alzheimer's disease. , method. 16. A method of delivering an agent of interest to a CD71 positive cell, comprising contacting the cell with an agent of interest coupled to a FN3 domain that binds to CD71, such as the polypeptide of any one of claims 1-15. . 36. The method of claim 35, wherein the agent of interest is internalized into the cell through CD71-mediated interaction. 36. The method of claim 35, wherein the FN3 domain does not compete with transferrin binding to CD71. 38. The method of any one of claims 33 to 37, wherein the agent of interest is a chemotherapeutic agent, drug, growth inhibitor, toxin, radioisotope, anti-tubulin agent, polynucleotide, siRNA molecule, antisense molecule, RNA molecule, Method, which is a DNA molecule, DNA minor groove binder, DNA replication inhibitor, alkylating agent, antibiotic, antifolate agent, antimetabolite, chemotherapy sensitizer, topoisomerase inhibitor or vinca alkaloid. The method of any one of claims 35 to 38, wherein the FN3 domain comprises the sequence of SEQ ID NOs: 1 to 7, 10, 12 to 219, 221 to 272, 292 to 299, or 304 to 306. 40. The method of any one of claims 35 to 39, wherein the cells are muscle cells. 40. The method of any one of claims 35 to 39, wherein the cells are brain cells or cells within the blood brain barrier. As a method of identifying FN3 protein that binds to CD71 at a site that does not compete with or inhibit transferrin binding to CD71,
contacting the CD71 with a test FN3 protein in the presence of transferrin or an agent that binds to the CD71 transferrin binding site; and
Identifying the test FN3 protein binding to CD71 in the presence of transferrin or an agent that binds to the CD71 transferrin binding site.
Method, including. 43. The method of claim 42, further comprising isolating the test FN3 protein that binds to CD71 in the presence of transferrin or an agent that binds to the CD71 transferrin binding site. 44. The method of claim 42 or 43, further comprising sequencing the test FN3 protein that binds to CD71 in the presence of transferrin or an agent that binds to the CD71 transferrin binding site. 45. The method of any one of claims 42 to 44, further comprising preparing or obtaining a nucleic acid sequence encoding said test FN3 protein that binds to CD71 in the presence of transferrin or an agent that binds to said CD71 transferrin binding site. How to. 46. The method of any one of claims 42 to 45, wherein a nucleic acid sequence encoding said test FN3 protein binds to CD71 in the presence of transferrin or an agent that binds to said CD71 transferrin binding site. The method further comprising expressing the test FN3 protein that binds CD71 in the presence of a binding agent. 47. The method of claim 46, wherein the test FN3 protein is expressed in the cell. 47. The method of claim 46, further comprising isolating and/or purifying the expressed test FN3 protein. A FN3 protein identified according to any one of claims 42 to 48. A pharmaceutical composition comprising the FN3 protein of claim 49. An isolated polynucleotide encoding the polypeptide of claim 49. A vector containing the polynucleotide of claim 51. A host cell comprising the vector of claim 52.